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Contents lists available at ScienceDirect
The International Journal of Biochemistry & Cell Biology journal homepage: www.elsevier.com/locate/biocel
Review
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MicroRNAs mediated targeting on the Yin-yang dynamics of DNA methylation in disease and development夽
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Jiajie Tu a,b,∗ , Jason Jinyue Liao a,b , Alfred Chun Shui Luk a,b , Nelson Leung Sang Tang c , Wai-Yee Chan a,b , Tin-Lap Lee a,b a Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, The Chinese University of Hong Kong,Shatin, N.T., Hong Kong Special Administrative Region b Shandong University (CUHK-SDU) Joint Laboratory on Reproductive Genetics, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region c Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region
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Article history: Received 9 April 2015 Received in revised form 30 April 2015 Accepted 2 May 2015 Available online xxx
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Keywords: microRNA Epigenetics DNA demethylation pathway Histone modification
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Contents
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For decades, DNA methylation at the 5 position of cytosine (5mC) catalyzed by DNA methyltransferases (DNMTs) is a well-known epigenetic modification in mammalian genome, where it modulates chromatin remodeling and transcriptional silencing. The discovery of Ten-eleven translocation (TET) enzymes that oxidize 5mC to 5-hydroxymethylcytosine (5hmC) prompts a new era of DNA demethylation research. It is now established that in DNA demethylation pathway 5mC is first converted to 5-hydroxymethylcytosine (5hmC), then 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) through TETs. Conversion to unmethylated cytosine (5C) is further facilitated by excision mechanism through thymine-DNA glycosylase (TDG) or base excision repair (BER) pathway. Our understanding of DNMTs and TETs on epigenetic dynamics of cytosine methylation has led to a completion of the methylation (Yin) – demethylation (Yang) cycle on epigenetic modifications on cytosine. However, the regulations on DNA demethylation pathway remain largely unknown. In this review, we provide the recent advances on epigenetic dynamics of DNA demethylation and its potential control from the prespective of small noncoding RNA-mediated regulation. Specifically, we will illustrate how microRNAs contribute to active DNA demethylation control in normal and disease development based on recent findings in stem cells and cancer. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. © 2015 Published by Elsevier Ltd.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular regulations of TETs in DNA demethylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. DNA demethylation pathway in stem cells development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. DNA demethylation pathway in cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The roles of microRNAs in DNA demethylation pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. MiR-22 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. MiR-26 cluster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. MiR-29 cluster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: 5mC, 5-methylcytosine; 5hmC, 5-hydroxymethylcytosine; 5fC, 5-formalcytosine; 5caC, 5-carboxylcytosine; DNMTs, DNA methyltransferases; TET, Teneleven translocation family; TDG, thymine-DNA glycosylase; PRC, polycomb repressive complex; H3K27me3, trimethylation of lysine 27 on histone H3; BER, base excision repair. 夽 This article is part of a directed issue entitled: Epigenetics dynamics in development and disease. ∗ Corresponding author at: 622A, Lo Kwee-Seong Integrated Biomedical Sciences Building, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region. Tel.: +852 39434436; fax: +852 26035139. E-mail address: [email protected] (J. Tu). http://dx.doi.org/10.1016/j.biocel.2015.05.002 1357-2725/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: Tu J, et al. MicroRNAs mediated targeting on the Yin-yang dynamics of DNA methylation in disease and development. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.05.002
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1. Introduction
Epigenetic modifications in mammalian genome represents an important hallmark in normal and disease development. Among 40 the modifications, DNA methylation at the 5-cytosine (5C) reside in 41 form of 5 methylcytosine (5mC) established by DNA methyltrans42 ferases (DNMTs) has been extensively studied for the past decades. 43 It has established that the presence of 5mC at the CG rich region 44 (CpG island) is usually associated with transcriptional regulations. 45 Dynamic alteration of DNA methylation pattern on genome-wide 46 or specific gene loci is essential for normal development, such as 47 imprinting, differentiation and tissue specification during embry48 oic development. Therefore, aberrant DNA methylation on key 49 regulatory genes or pathways could lead to developmental fail50 ure or disease development. For example, aberrant methylation of 51 tumor suppressor genes contributes to their transcriptional silenc52 ing in the pathogenesis of various human tumors (Goll and Bestor, 53 2005). Reversal of DNA methylation by demethylating cytidine 54 analogs like 5-azacytidine (azacitidine) and 5-azadeoxycytidine 55 (decitabine) have been shown to be effective in cancer treatment, 56 and has been approved for treating myelodysplastic syndrome 57 (MDS) by Food and Drug Administration (FDA) in the United 58 States. 59 Compared to DNA methylation, the mechanisms of DNA 60 demethylation on methylated cytosine to unmethylated cytosine 61 (5mC to 5C), however, is relatively less studied. Passive DNA 62 demethylation occurs on strand-specific manner during DNA repli63 cation, but the existence of active DNA methylation has long 64 been sought by scientists. The discovery of Ten-eleven transloca65 tion (TET) enzymes that oxidize 5mC to 5-hydroxymethylcytosine 66 (5hmC) in 2009 prompted a new era of DNA demethylation 67 research. Interestingly, the presence of 5-hydroxymethylcytosine 68 (5hmC) has been detected in bacteria since 1950s and later in 69 mammals in the 1970s. However, the significance of this modified70 cytosine, now known as the “sixth” base, went unrecognized until 71 recently (Wyatt and Cohen, 1953; Penn et al., 1972). It is now estab72 lished that 5mC is first converted to 5-hydroxymethyl cytosine 73 (5hmC), then 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) 74Q3 through TETs (Ito et al., 2011). Conversion to unmethylated cytosine 75 (5C) is further facilitated by excision mechanism through thymine76 DNA glycosylase (TDG) or base excision repair (BER) pathway (Ito 77 et al., 2010) (Kriaucionis and Heintz, 2009; Kohli and Zhang, 2013). 78 Our understanding of DNMTs and TETs on epigenetic dynamics of 79 cytosine methylation has led to a completion of the methylation 80 (Yin) – demethylation (Yang) cycle on epigenetic modifications on 81 cytosine (Fig. 1). 82 Yet the intriguing findings come with more questions than 83 answers. For instance, why evolution retains three different TET 84 proteins when they appears to function in similar function? For the 85 three TET members identified so far, they all feature a (Cys-rich and 86 DSBH regions) domain that catalyze the conversion of 5mC–5hmC. 87 Another CXXC domain is found in TET1 and TET3. Its exact role is 88 not fully understood, but it is suggested for target recognition in the 89 genome. Emerging evidence has suggested each TET member actu90 ally exhibits unique functional role in tissue and functional-specific 91 epigenetic control, which is supported by difference on expression 92 levels and cell-type distribution. TET1/2 are found in embryonic 93 stem cells, while TET3 is found in the germ line (Ito et al., 2010). 94 The significance of these differences, and the mechanisms of how 95 TETs are regulated remain largely unknown. In this short review, 96 we provide the recent advances on epigenetic dynamics of DNA 97 demethylation and its potential control from the perspective of 98 non-coding RNA-mediated regulation. Specially, we will illustrate 99 how microRNAs contribute to active DNA demethylation control in 100 normal and disease development based on recent findings in stem 101 cells and cancer. 38Q2 39
Fig. 1. DNA demethylation signaling pathway. The Yin-Yang cycle of DNA methylation comprises of a number of important enzymes. DNMTs first methylate 5 -position cytosine to 5-methylcytosine (5mC). TETs successively oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5fC and 5caC can be excised and repaired to regenerate unmodified cytosines by base excision repair (BER) pathway thymine-DNA glycosylase (TDG). CXXC (binding domain, direct binds CpG islands); CD (catalytic domain, containing the Cys-rich and DSBH regions); UDG (Uracil-DNA glycosylase, regulatory domain).
2. Molecular regulations of TETs in DNA demethylation It was once speculated that 5hmC just plays the opposite role of 5mC in DNA demethylation pathway in view of structural difference (Xu et al., 2011). 5hmC enrichment at promoter and gene body was reported to positively correlate with target gene expression (Ficz et al., 2011). However, recent studies show such assumption is over-simplified. Emerging evidence from recent studies have suggested the DNA demethylation pathway appears to be more complex than previously envisioned, which can be exemplified in stem cell and cancer models. 2.1. DNA demethylation pathway in stem cells development The three TET members display differential expression patterns in different stem cells types and at different differentiation stages. Tet1 is the most abundantly expressed TET member in ESCs, while Tet3 expresses at very basal level (Koh et al., 2011). 5hmC level in stem cells is enriched in promoters, gene bodies, and intergenic areas near genes and positively correlates with gene expression at these loci (Pastor et al., 2011; Song et al., 2011; Xu et al., 2011). The 5hmC marks appear to promote gene expression during active demethylation. It is hypothesized that conversion of 5mC–5hmC by TETs blocks the repressive MBD-domain containing proteins and DNMTs recruited to the 5mC sites (Branco et al., 2011). As expected, reduced Tet1 or Tet2 decreases cellular 5hmC levels and subsequently 5hmC cause impaired self-renewal (Koh et al., 2011; Freudenberg et al., 2012). Upon ESCs differentiation, the levels of Tet1/Tet2 decrease and Tet3 increases; global 5hmC also decreases correspondingly, which suggesting that Tet1- and Tet2-mediated 5hmC is strongly correlated with the maintenance of ESC pluripotency. In agreement with this, one study found that Tet1 depletion impaired the self-renewal of ESCs (Ito et al., 2010). Tet1 and Tet2 were also found to associate with the pluripotency factor Nanog and increase reprogramming efficiency synergistically (Costa et al., 2013). Other studies found that the pluripotency factor Oct4/Sox2 complex regulates the expression of Tet1 and Tet2, and the
Please cite this article in press as: Tu J, et al. MicroRNAs mediated targeting on the Yin-yang dynamics of DNA methylation in disease and development. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.05.002
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depletion of Tet1 skewed the differentiation of ESCs (Koh et al., 2011; Williams et al., 2011). 5hmC could also potentially interact with histone marks to regulate gene expression in human ESCs, making it important for cell identity. For example, 5hmC-enriched enhancers are enriched with H3K4me1, H3K9ac, and H3K27ac (Szulwach et al., 2011). It also appears that the binding of TETs to their genomic loci is not in random fashion. For example, Tet1 preferentially binds to genomic regions with intermediate and high CpG density, and Tet1 binding sites are enriched at promoters, exons, and TSS regions (Xu et al., 2011). Based on different adjacent histone marks, Tet1 binding promoters can be divided into three categories: (1) actively transcribed genes marked by H3K4me3, (2) negatively transcribed genes marked by H3K27me3, and (3) bivalent genes marked by H3K27me3 and H3K4me3 (Wu et al., 2011). Different histone marks have different effect on target genes, it may explain the multifunction of TET family in DNA demethylation pathway. 2.2. DNA demethylation pathway in cancer It has long believed that aberrant DNA methylation profile caused by abnormal DNMTs enzymes is a major hallmark of cancer. However, recent study shows DNMT3a and DNMT3b can work as DNA methyltransferases and dehydroxymethylases. Such bidirectional aspect poses a whole host of new questions about these enzymes and how they regulate genomic modifications during development, carcinogenesis, and gene regulation (Chen et al., 2012). The discovery of 5hmC, 5fC and 5caC further prompts a re-evaluation of the relationship between DNA demethylation and cancer development, as it raises the possibility that impaired function of the demethylation pathway could equally lead to an imbalance of DNA methylation status. Indeed, 5hmC is largely depleted in several human cancer cells compared with normal tissues, and the expression of TET is substantially reduced. Specifically, global 5hmC and TET1 was significantly repressed in gastric cancers and colorectal cancers (Kudo et al., 2012). TET2 is frequently mutated or inactivated in leukemia, but is required for normal hematopoiesis (Li et al., 2011). Rmpal et al. recently found that WT1-mutant AMLs have similar 5hmC alterations to IDH1/2 and TET2 mutants which provides a role for WT1 in regulating 5hmC and suggests that TET2, IDH1/2 and WT1 mutations define an AML subtype defined by dysregulated 5hmC (Rampal et al., 2014). Another excellent paper also showed that loss of 5hmC is an epigenetic hallmark of melanoma (Lian et al., 2012). Together, these recent observations suggested that functionally active demethylation pathway is crucial in maintaining the dynamic balance between DNA methylation and demethylation and in inhibiting tumor progression. 5hmC and TET family maybe considered as biomarkers of tumorigenesis and applied in the early diagnosis and prognosis of digestive tumor. Two groups further mapped 5fC landscape at a genome-wide level in mESCs and found that TDG specifically recognizes 5fC (Shen et al., 2013; Song et al., 2013a). TDG depletion significantly induces global levels of 5fC and 5caC. ∼20% 5fC-enriched regions localized to enhancers, particularly at poised enhancers marked with H3K4me1 (Song et al., 2013a). TDG knockout mESCs did not display any abnormal in morphology and only showed subtle alterations in some genes expression (Shen et al., 2013). Thus, further exploration is needed to fully discover role of 5fC and 5caC in ESCs. 3. The roles of microRNAs in DNA demethylation pathway The discovery of small non-coding RNAs (∼22 nucleotides) have revolutionized our view of regulatory networks within eukaryotic cells in the past decade (Bartel, 2004). MicroRNAs are small
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non-coding RNAs that negatively modulate gene expression through binding to the 3 untranslated region of target messenger RNAs. A complete complementary binding of microRNA to its target sequence can lead to direct endonucleolytic mRNA cleavage, whereas partial complementary binding of a mature microRNA affects the stability of the target mRNA leading to transcriptional inhibition. The number of human and mouse microRNAs in miRBase (www.mirbase.org) has reached to almost 1900 and 1200 respectively. MicroRNAs regulate a wide variety of physiological and developmental processes (Yates et al., 2013). Dysregulation of microRNA expression is involved in a number of diseases including developmental disorders, neurological diseases, cardiovascular disorders, as well as cancer (Sayed and Abdellatif, 2011; Jansson and Lund, 2012). As both microRNAs and epigenetic regulations actively contribute both normal and disease development, the possible existence of a regulatory circuit between epigenetic modulation by microRNAs (and vice versa) was investigated. It turns out a subset of microRNAs target the key enzymes involved in DNA methylation dynamics (DNMTs, TETs and TDG) directly or indirectly through other regulators, such as PRC2. This class of microRNA is collectively referred as epi-miRNAs. In contrast, the presence of CpG islands next to half of microRNA species suggests that they could be subjected to epigenetic regulation by DNA methylation (Weber et al., 2014), which has been demonstrated in studies by us and others (Cheung et al., 2011; Iorio et al., 2010). Both epi-miRNAs and epigenetically modulated microRNAs create a highly controlled feedback mechanism in dynamic regulation of DNA methylation. A number of epi-miRNAs has been revealed to involve in DNA demethylation dynamics, including miR-22, miR-26, and miR-29. These microRNA candidates target the key regulators in epigenetic modifications of DNA and histones in cancer and development (Song et al., 2013b; Morita et al., 2013; Fu et al., 2013) (Fig. 2). 3.1. MiR-22 MiR-22 was recently suggested to be a dual regulator of selfrenewal machinery and oncogenesis via direct targeting of Tet1 and Tet2. Song et al. (2013c) showed that miR-22 induces epithelial cells to acquire features of epithelial-to-mesenchymal transition (EMT). MiR-22 is positively associated with expression of oncogenes and the number of mammary stem/progenitor cells, which can reconstitute to mammary epithelial trees. These changes are followed by spontaneous neoplastic transformation of normal mouse breast epithelia into metastatic breast carcinomas. When combined with other additional oncogenic insults, miR-22 accelerates both tumor progression and metastasis. Subsequent report by the same group demonstrated miR-22 overexpression increased proliferation of hematopoietic stem/progenitor cells (HSPCs) (Song et al., 2013b). In addition, transplanted HSPCs overexpressing miR-22 gave rise to a disease reminiscent of a myelodisplastic (MS) syndrome, which subsequently progressed to full-blown AML (Fig. 3). Q4 In both the mammary epithelium and the hematopoietic systems, the biological effects of miR-22 were mediated by its capacity to suppress of TET family members. Indeed, genetic inactivation of TET proteins has been shown to disrupt the epigenetic remodeling during normal differentiation, and TET mutations are commonly observed in human hematological malignancies (Abdel-Wahab et al., 2009). Similar to overexpression of miR-22, Tet2 inactivation in mice is associated with a HSPCs expansion and neoplastic transformation (Cimmino et al., 2011). The study also showed that miR-22 overexpression is associated with hypermethylation and epigenetic silencing in promoter of another miRNA, miR-200c. This is accompanied by upregulation of Bmi1, a key member of the Polycomb group protein family (PRC1) involved in self-renewal machinery in both hematopoietic and mammary epithelial stem
Please cite this article in press as: Tu J, et al. MicroRNAs mediated targeting on the Yin-yang dynamics of DNA methylation in disease and development. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.05.002
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Fig. 2. MiRNA-regulated epigenetic regulation between stem cell and cancer cell. The regulatory network between two epigenetic modifications (histone/DNA modifications and their corresponding catalytic proteins, PRC1/2 for histone modification; DNMTs, TETs and TDG for DNA methylation/demethylation circle) and three epi-miRNAs (miR-22, miR-26 and miR-29). The proved direct connections between different proteins are also shown.
Fig. 3. The proposed “Yin-Yang” model for genomic regulation of DNMT/TET/TDG mediated methylation/demethylation circle. DNA methylation patterns are dynamically balanced by methylation and demethylation processes. Transcriptional repression by DNA methylation (DNMTs) could lead to transcriptional remodeling at key anti-cancer genes. The promoter regions of these genes gain 5hmC and these changes ultimately lead to the aberrant methylation pattern seen in cancer. DNMTi, DNA methyltransferase inhibitor; MiRNAi, microRNA inhibitor; TETa, Ten-eleven translocation protein activator; TDGa, thymine-DNA glycosylase activator.
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cells (Pietersen et al., 2008). Delineating how these epigenetic pathways interact each other is a fundamental step toward the understanding of stem cell homeostasis and tumor initiation.
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MiR-26 cluster is another interesting epi-miRNA that associates with stem cells development and cancer progression through inactivation of DNA demethylation pathway. Previously, study has suggested miRNA-26 cooperate with other epigenetic regulator during osteogenic differentiation (Luzi et al., 2007), and inducing myogenesis via silencing the negative regulator of myogenesis EZH2 (Enhancer of Zeste Homolog 2, a key subunit of PRC2 complex) (Wong and Tellam, 2008). Recently, Fu XH et al. showed that miR-26a could directly target TETs and decrease 5hmC levels in pancreatic cells. miR-26a promotes pancreatic stem cell differentiation both in vitro and in vivo, which delineate a relation between miRNA, 5hmC and stem cell differentiation (Fu et al., 2013). In our
recent study, we also identified both miR-26a and miR-26b could repress Tet3 (the most abundant member of Tet family in testis) in spermatogonial stem cells, (SSCs) leading to reduced global 5hmC level (unpublished results). Stable expression of miR-26a and miR26b in SSCs promoted cellular differentiation. Taken together, these results highlight the promotion of pancreatic stem/progenitor cell differentiation and spermoatogenic progression through active epigenetic modulation induced by miR-26 cluster, which could be an alternative approach to increase the efficiency of pancreatic endocrine cells and sperm generation in vitro. Other than stem cell differentiation, miR-26 expression was reported to be repressed in various tumor types, which hints its potential role as a tumor-suppressor. MiR-26a was down-regulated in breast cancer specimens and cell lines (Zhang et al., 2011). It is required for initialization of apoptosis through endogenous and exogenous pathways through direct binding with EZH2. Importantly, EZH2 is the catalytic subunit of PRC2 complex, where it plays key role in PRC2-mediated histone modification, suggesting that miR-26 also could perform its role as an epigenetic regulator via modulating DNA methylation pathway and histone modification at the same time. Given the fact that Tet1 and PRC2 complex interacted in ESCs (Neri et al., 2013), it further confirming the possibility that miR-26 maybe functional as a dual epigenetic effector in ESCs via targeting Tet1 and PRC2 complex simultaneously.
3.3. MiR-29 cluster The most interesting point about miR-29 cluster is that it can target all three key enzymes (DNMTs, TETs and TDG) in DNA methylation/demethylation cycle. Previously, the miR-29 family were thought to suppress tumorigenesis by repressing de novo methylation. MiR-29 represses DNMT3A and DNMT3B expression in lung cancer tissues (Fabbri et al., 2007), and restores normal DNA methylation pattern in lung cancer cells via inducing of DNA methylation-silenced tumor suppressor genes, such as WWOX. These findings support a role of miR-29s in normalization of DNA methylation in Non-small cell lung cancer (NSCLC). While this idea was challenged until miR-29 was identified that could regulate other two key proteins in DNA demethylation pathway, TET and TDG (Zhang et al., 2013). Apart from the conventional role of “DNA methylation inhibitor”, miR-29 maybe also functional as an “extensive regulator” via regulation of all DNA modifications. MiR29 up-regulated the global DNA methylation level in some cancer
Please cite this article in press as: Tu J, et al. MicroRNAs mediated targeting on the Yin-yang dynamics of DNA methylation in disease and development. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.05.002
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cells and down-regulated DNA methylation in other cancer cells (Morita et al., 2013), suggesting that miR-29 modulates tumorigenesis by protecting against changes in the existing DNA methylation status rather than by preventing de novo methylation of DNA. Thus, just like miR-26 cluster, the role of miR-29 cluster in different tumors also depend on different targets. The role of miR-29 cluster in development has just began to emerge. We recently show ESC differentiation can be directed by non-coding RNA mediated epigenetic mechanism, which involves microRNA-29b (miR-29b) and Tet1. We also demonstrate miR29b/Tet1 regulatory axis contributes to mesendoderm lineage formation through Nodal signaling pathway by using in vitro and in vivo models. This novel regulatory axis also involves in repression of TDG, another important epigenetic regulator in active demethylation pathway. Our findings underscore the contribution of microRNA-mediated DNA demethylation dynamics and relate to key ectoderm and mesendoderm regulators during ESCs lineage specification. With this novel discovery, miR-29b could potentially be applied to enrich production of mesoderm and endoderm derivatives and be further differentiated into desired organ-specific cells. 4. Future prospects The discovery of active DNA demethylation pathway and the existence of microRNA modulation on the key regulators in DNA demethylation pathways have contributed significantly not only to an understanding of the molecular regulations but also provided new insights on epigenetic control during normal and disease development. Although global changes on DNA demethylation marks like 5hmC has been established in normal development and pathological states, its relationship with gene expression regulation remain elusive. There is a lot to be explored in the Yin-Yang cycle of DNA methylation, from how TETs divide their role in demethylation dynamics to how the subsequent modifications (5hmC, 5caC, 5fC) interact or get enriched with preferred genomic targets, chromatin remodeling complexes and epigenetic modifiers or modifications. With the advent of high-throughput genomic techniques like Oxidative Bisulfite Sequencing (OxBS-seq) (Booth et al., 2013) and TET-assisted Bisulfite Sequencing (TAB-seq) (Yu et al., 2012), DNA demethylation marks can be discriminated at single nucleotide resolution rapidly. Future studies are also required to elucidate the regulatory loop involving microRNAs and the epigenetic machinery, and investigate how to translate these findings into clinical applications. A better understanding of epigenetic regulatory mechanism of microRNA expression will help to elucidate the complex network of epigenetic modifications and design innovative strategies for regenerative medicine and cancer treatment. For example, the use of microRNAs or epigenetic editing (Chen et al., 2014) to either directly regulate gene expression, or to control the epigenetic machinery targeting the effector enzymes will create a promising perspective in biomedical sciences. References Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009;114(July (1)):144–7. Bartel DP. MicroRNAs: genomics, review biogenesis, mechanism, and function. Cell 2004;116(January (2)):281–97. Booth MJ, Ost TWB, Beraldi D, Bell NM, Branco MR, Reik W, et al. Oxidative bisulfite sequencing of 5-methylcytosine and 5-hydroxymethylcytosine. Nat Protoc 2013;8(September (10)):1841–51. Chen C-C, Wang K-Y, Shen C-KJ. The mammalian de novo DNA methyltransferases DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases. J Biol Chem 2012;287(September (40)):33116–21. Chen H, Kazemier HG, de Groote ML, Ruiters MHJ, Xu G-L, Rots MG. Induced DNA demethylation by targeting ten-eleven translocation 2 to the human ICAM-1
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Biochem J 1972;126: 781–90. Pietersen AM, Evers B, Prasad AA, Tanger E, Cornelissen-Steijger P, Jonkers J, et al. Bmi1 regulates stem cells and proliferation and differentiation of committed cells in mammary epithelium. Curr Biol 2008;18(July (14)):1094–9. Rampal R, Alkalin A, Madzo J, Vasanthakumar A, Pronier E, Patel J, et al. DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia. Cell Rep 2014;9(December (5)):1841–55. Sayed D, Abdellatif M. MicroRNAs in development and disease. Physiol Rev 2011;91(July (3)):827–87. Shen L, Wu H, Diep D, Yamaguchi S, D’Alessio AC, Fung H-L, et al. Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell 2013;153(April (3)):692–706. Song C-X, Szulwach KE, Dai Q, Fu Y, Mao S-Q, Lin L, et al. Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell 2013a;153(April (3)):678–91. Song SJ, Ito K, Ala U, Kats L, Webster K, Sun SM, et al. The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell 2013b;13(July (1)): 87–101. Song SJ, Poliseno L, Song MS, Ala U, Webster K, Ng C, et al. MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 2013c;154(July (2)):311–24. Szulwach KE, Li X, Li Y, Song C-X, Han JW, Kim S, et al. Integrating 5hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet 2011;7(June (6)):e1002154.
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MicroRNAs mediated targeting on the Yin-yang dynamics of DNA methylation in disease and development夽
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Jiajie Tu a,b,∗ , Jason Jinyue Liao a,b , Alfred Chun Shui Luk a,b , Nelson Leung Sang Tang c , Wai-Yee Chan a,b , Tin-Lap Lee a,b a Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, The Chinese University of Hong Kong,Shatin, N.T., Hong Kong Special Administrative Region b Shandong University (CUHK-SDU) Joint Laboratory on Reproductive Genetics, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region c Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region
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Article history: Received 9 April 2015 Received in revised form 30 April 2015 Accepted 2 May 2015 Available online xxx
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Keywords: microRNA Epigenetics DNA demethylation pathway Histone modification
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For decades, DNA methylation at the 5 position of cytosine (5mC) catalyzed by DNA methyltransferases (DNMTs) is a well-known epigenetic modification in mammalian genome, where it modulates chromatin remodeling and transcriptional silencing. The discovery of Ten-eleven translocation (TET) enzymes that oxidize 5mC to 5-hydroxymethylcytosine (5hmC) prompts a new era of DNA demethylation research. It is now established that in DNA demethylation pathway 5mC is first converted to 5-hydroxymethylcytosine (5hmC), then 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) through TETs. Conversion to unmethylated cytosine (5C) is further facilitated by excision mechanism through thymine-DNA glycosylase (TDG) or base excision repair (BER) pathway. Our understanding of DNMTs and TETs on epigenetic dynamics of cytosine methylation has led to a completion of the methylation (Yin) – demethylation (Yang) cycle on epigenetic modifications on cytosine. However, the regulations on DNA demethylation pathway remain largely unknown. In this review, we provide the recent advances on epigenetic dynamics of DNA demethylation and its potential control from the prespective of small noncoding RNA-mediated regulation. Specifically, we will illustrate how microRNAs contribute to active DNA demethylation control in normal and disease development based on recent findings in stem cells and cancer. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. © 2015 Published by Elsevier Ltd.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular regulations of TETs in DNA demethylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. DNA demethylation pathway in stem cells development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. DNA demethylation pathway in cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The roles of microRNAs in DNA demethylation pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. MiR-22 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. MiR-26 cluster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. MiR-29 cluster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: 5mC, 5-methylcytosine; 5hmC, 5-hydroxymethylcytosine; 5fC, 5-formalcytosine; 5caC, 5-carboxylcytosine; DNMTs, DNA methyltransferases; TET, Teneleven translocation family; TDG, thymine-DNA glycosylase; PRC, polycomb repressive complex; H3K27me3, trimethylation of lysine 27 on histone H3; BER, base excision repair. 夽 This article is part of a directed issue entitled: Epigenetics dynamics in development and disease. ∗ Corresponding author at: 622A, Lo Kwee-Seong Integrated Biomedical Sciences Building, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region. Tel.: +852 39434436; fax: +852 26035139. E-mail address: [email protected] (J. Tu). http://dx.doi.org/10.1016/j.biocel.2015.05.002 1357-2725/© 2015 Published by Elsevier Ltd.
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1. Introduction
Epigenetic modifications in mammalian genome represents an important hallmark in normal and disease development. Among 40 the modifications, DNA methylation at the 5-cytosine (5C) reside in 41 form of 5 methylcytosine (5mC) established by DNA methyltrans42 ferases (DNMTs) has been extensively studied for the past decades. 43 It has established that the presence of 5mC at the CG rich region 44 (CpG island) is usually associated with transcriptional regulations. 45 Dynamic alteration of DNA methylation pattern on genome-wide 46 or specific gene loci is essential for normal development, such as 47 imprinting, differentiation and tissue specification during embry48 oic development. Therefore, aberrant DNA methylation on key 49 regulatory genes or pathways could lead to developmental fail50 ure or disease development. For example, aberrant methylation of 51 tumor suppressor genes contributes to their transcriptional silenc52 ing in the pathogenesis of various human tumors (Goll and Bestor, 53 2005). Reversal of DNA methylation by demethylating cytidine 54 analogs like 5-azacytidine (azacitidine) and 5-azadeoxycytidine 55 (decitabine) have been shown to be effective in cancer treatment, 56 and has been approved for treating myelodysplastic syndrome 57 (MDS) by Food and Drug Administration (FDA) in the United 58 States. 59 Compared to DNA methylation, the mechanisms of DNA 60 demethylation on methylated cytosine to unmethylated cytosine 61 (5mC to 5C), however, is relatively less studied. Passive DNA 62 demethylation occurs on strand-specific manner during DNA repli63 cation, but the existence of active DNA methylation has long 64 been sought by scientists. The discovery of Ten-eleven transloca65 tion (TET) enzymes that oxidize 5mC to 5-hydroxymethylcytosine 66 (5hmC) in 2009 prompted a new era of DNA demethylation 67 research. Interestingly, the presence of 5-hydroxymethylcytosine 68 (5hmC) has been detected in bacteria since 1950s and later in 69 mammals in the 1970s. However, the significance of this modified70 cytosine, now known as the “sixth” base, went unrecognized until 71 recently (Wyatt and Cohen, 1953; Penn et al., 1972). It is now estab72 lished that 5mC is first converted to 5-hydroxymethyl cytosine 73 (5hmC), then 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) 74Q3 through TETs (Ito et al., 2011). Conversion to unmethylated cytosine 75 (5C) is further facilitated by excision mechanism through thymine76 DNA glycosylase (TDG) or base excision repair (BER) pathway (Ito 77 et al., 2010) (Kriaucionis and Heintz, 2009; Kohli and Zhang, 2013). 78 Our understanding of DNMTs and TETs on epigenetic dynamics of 79 cytosine methylation has led to a completion of the methylation 80 (Yin) – demethylation (Yang) cycle on epigenetic modifications on 81 cytosine (Fig. 1). 82 Yet the intriguing findings come with more questions than 83 answers. For instance, why evolution retains three different TET 84 proteins when they appears to function in similar function? For the 85 three TET members identified so far, they all feature a (Cys-rich and 86 DSBH regions) domain that catalyze the conversion of 5mC–5hmC. 87 Another CXXC domain is found in TET1 and TET3. Its exact role is 88 not fully understood, but it is suggested for target recognition in the 89 genome. Emerging evidence has suggested each TET member actu90 ally exhibits unique functional role in tissue and functional-specific 91 epigenetic control, which is supported by difference on expression 92 levels and cell-type distribution. TET1/2 are found in embryonic 93 stem cells, while TET3 is found in the germ line (Ito et al., 2010). 94 The significance of these differences, and the mechanisms of how 95 TETs are regulated remain largely unknown. In this short review, 96 we provide the recent advances on epigenetic dynamics of DNA 97 demethylation and its potential control from the perspective of 98 non-coding RNA-mediated regulation. Specially, we will illustrate 99 how microRNAs contribute to active DNA demethylation control in 100 normal and disease development based on recent findings in stem 101 cells and cancer. 38Q2 39
Fig. 1. DNA demethylation signaling pathway. The Yin-Yang cycle of DNA methylation comprises of a number of important enzymes. DNMTs first methylate 5 -position cytosine to 5-methylcytosine (5mC). TETs successively oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5fC and 5caC can be excised and repaired to regenerate unmodified cytosines by base excision repair (BER) pathway thymine-DNA glycosylase (TDG). CXXC (binding domain, direct binds CpG islands); CD (catalytic domain, containing the Cys-rich and DSBH regions); UDG (Uracil-DNA glycosylase, regulatory domain).
2. Molecular regulations of TETs in DNA demethylation It was once speculated that 5hmC just plays the opposite role of 5mC in DNA demethylation pathway in view of structural difference (Xu et al., 2011). 5hmC enrichment at promoter and gene body was reported to positively correlate with target gene expression (Ficz et al., 2011). However, recent studies show such assumption is over-simplified. Emerging evidence from recent studies have suggested the DNA demethylation pathway appears to be more complex than previously envisioned, which can be exemplified in stem cell and cancer models. 2.1. DNA demethylation pathway in stem cells development The three TET members display differential expression patterns in different stem cells types and at different differentiation stages. Tet1 is the most abundantly expressed TET member in ESCs, while Tet3 expresses at very basal level (Koh et al., 2011). 5hmC level in stem cells is enriched in promoters, gene bodies, and intergenic areas near genes and positively correlates with gene expression at these loci (Pastor et al., 2011; Song et al., 2011; Xu et al., 2011). The 5hmC marks appear to promote gene expression during active demethylation. It is hypothesized that conversion of 5mC–5hmC by TETs blocks the repressive MBD-domain containing proteins and DNMTs recruited to the 5mC sites (Branco et al., 2011). As expected, reduced Tet1 or Tet2 decreases cellular 5hmC levels and subsequently 5hmC cause impaired self-renewal (Koh et al., 2011; Freudenberg et al., 2012). Upon ESCs differentiation, the levels of Tet1/Tet2 decrease and Tet3 increases; global 5hmC also decreases correspondingly, which suggesting that Tet1- and Tet2-mediated 5hmC is strongly correlated with the maintenance of ESC pluripotency. In agreement with this, one study found that Tet1 depletion impaired the self-renewal of ESCs (Ito et al., 2010). Tet1 and Tet2 were also found to associate with the pluripotency factor Nanog and increase reprogramming efficiency synergistically (Costa et al., 2013). Other studies found that the pluripotency factor Oct4/Sox2 complex regulates the expression of Tet1 and Tet2, and the
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depletion of Tet1 skewed the differentiation of ESCs (Koh et al., 2011; Williams et al., 2011). 5hmC could also potentially interact with histone marks to regulate gene expression in human ESCs, making it important for cell identity. For example, 5hmC-enriched enhancers are enriched with H3K4me1, H3K9ac, and H3K27ac (Szulwach et al., 2011). It also appears that the binding of TETs to their genomic loci is not in random fashion. For example, Tet1 preferentially binds to genomic regions with intermediate and high CpG density, and Tet1 binding sites are enriched at promoters, exons, and TSS regions (Xu et al., 2011). Based on different adjacent histone marks, Tet1 binding promoters can be divided into three categories: (1) actively transcribed genes marked by H3K4me3, (2) negatively transcribed genes marked by H3K27me3, and (3) bivalent genes marked by H3K27me3 and H3K4me3 (Wu et al., 2011). Different histone marks have different effect on target genes, it may explain the multifunction of TET family in DNA demethylation pathway. 2.2. DNA demethylation pathway in cancer It has long believed that aberrant DNA methylation profile caused by abnormal DNMTs enzymes is a major hallmark of cancer. However, recent study shows DNMT3a and DNMT3b can work as DNA methyltransferases and dehydroxymethylases. Such bidirectional aspect poses a whole host of new questions about these enzymes and how they regulate genomic modifications during development, carcinogenesis, and gene regulation (Chen et al., 2012). The discovery of 5hmC, 5fC and 5caC further prompts a re-evaluation of the relationship between DNA demethylation and cancer development, as it raises the possibility that impaired function of the demethylation pathway could equally lead to an imbalance of DNA methylation status. Indeed, 5hmC is largely depleted in several human cancer cells compared with normal tissues, and the expression of TET is substantially reduced. Specifically, global 5hmC and TET1 was significantly repressed in gastric cancers and colorectal cancers (Kudo et al., 2012). TET2 is frequently mutated or inactivated in leukemia, but is required for normal hematopoiesis (Li et al., 2011). Rmpal et al. recently found that WT1-mutant AMLs have similar 5hmC alterations to IDH1/2 and TET2 mutants which provides a role for WT1 in regulating 5hmC and suggests that TET2, IDH1/2 and WT1 mutations define an AML subtype defined by dysregulated 5hmC (Rampal et al., 2014). Another excellent paper also showed that loss of 5hmC is an epigenetic hallmark of melanoma (Lian et al., 2012). Together, these recent observations suggested that functionally active demethylation pathway is crucial in maintaining the dynamic balance between DNA methylation and demethylation and in inhibiting tumor progression. 5hmC and TET family maybe considered as biomarkers of tumorigenesis and applied in the early diagnosis and prognosis of digestive tumor. Two groups further mapped 5fC landscape at a genome-wide level in mESCs and found that TDG specifically recognizes 5fC (Shen et al., 2013; Song et al., 2013a). TDG depletion significantly induces global levels of 5fC and 5caC. ∼20% 5fC-enriched regions localized to enhancers, particularly at poised enhancers marked with H3K4me1 (Song et al., 2013a). TDG knockout mESCs did not display any abnormal in morphology and only showed subtle alterations in some genes expression (Shen et al., 2013). Thus, further exploration is needed to fully discover role of 5fC and 5caC in ESCs. 3. The roles of microRNAs in DNA demethylation pathway The discovery of small non-coding RNAs (∼22 nucleotides) have revolutionized our view of regulatory networks within eukaryotic cells in the past decade (Bartel, 2004). MicroRNAs are small
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non-coding RNAs that negatively modulate gene expression through binding to the 3 untranslated region of target messenger RNAs. A complete complementary binding of microRNA to its target sequence can lead to direct endonucleolytic mRNA cleavage, whereas partial complementary binding of a mature microRNA affects the stability of the target mRNA leading to transcriptional inhibition. The number of human and mouse microRNAs in miRBase (www.mirbase.org) has reached to almost 1900 and 1200 respectively. MicroRNAs regulate a wide variety of physiological and developmental processes (Yates et al., 2013). Dysregulation of microRNA expression is involved in a number of diseases including developmental disorders, neurological diseases, cardiovascular disorders, as well as cancer (Sayed and Abdellatif, 2011; Jansson and Lund, 2012). As both microRNAs and epigenetic regulations actively contribute both normal and disease development, the possible existence of a regulatory circuit between epigenetic modulation by microRNAs (and vice versa) was investigated. It turns out a subset of microRNAs target the key enzymes involved in DNA methylation dynamics (DNMTs, TETs and TDG) directly or indirectly through other regulators, such as PRC2. This class of microRNA is collectively referred as epi-miRNAs. In contrast, the presence of CpG islands next to half of microRNA species suggests that they could be subjected to epigenetic regulation by DNA methylation (Weber et al., 2014), which has been demonstrated in studies by us and others (Cheung et al., 2011; Iorio et al., 2010). Both epi-miRNAs and epigenetically modulated microRNAs create a highly controlled feedback mechanism in dynamic regulation of DNA methylation. A number of epi-miRNAs has been revealed to involve in DNA demethylation dynamics, including miR-22, miR-26, and miR-29. These microRNA candidates target the key regulators in epigenetic modifications of DNA and histones in cancer and development (Song et al., 2013b; Morita et al., 2013; Fu et al., 2013) (Fig. 2). 3.1. MiR-22 MiR-22 was recently suggested to be a dual regulator of selfrenewal machinery and oncogenesis via direct targeting of Tet1 and Tet2. Song et al. (2013c) showed that miR-22 induces epithelial cells to acquire features of epithelial-to-mesenchymal transition (EMT). MiR-22 is positively associated with expression of oncogenes and the number of mammary stem/progenitor cells, which can reconstitute to mammary epithelial trees. These changes are followed by spontaneous neoplastic transformation of normal mouse breast epithelia into metastatic breast carcinomas. When combined with other additional oncogenic insults, miR-22 accelerates both tumor progression and metastasis. Subsequent report by the same group demonstrated miR-22 overexpression increased proliferation of hematopoietic stem/progenitor cells (HSPCs) (Song et al., 2013b). In addition, transplanted HSPCs overexpressing miR-22 gave rise to a disease reminiscent of a myelodisplastic (MS) syndrome, which subsequently progressed to full-blown AML (Fig. 3). Q4 In both the mammary epithelium and the hematopoietic systems, the biological effects of miR-22 were mediated by its capacity to suppress of TET family members. Indeed, genetic inactivation of TET proteins has been shown to disrupt the epigenetic remodeling during normal differentiation, and TET mutations are commonly observed in human hematological malignancies (Abdel-Wahab et al., 2009). Similar to overexpression of miR-22, Tet2 inactivation in mice is associated with a HSPCs expansion and neoplastic transformation (Cimmino et al., 2011). The study also showed that miR-22 overexpression is associated with hypermethylation and epigenetic silencing in promoter of another miRNA, miR-200c. This is accompanied by upregulation of Bmi1, a key member of the Polycomb group protein family (PRC1) involved in self-renewal machinery in both hematopoietic and mammary epithelial stem
Please cite this article in press as: Tu J, et al. MicroRNAs mediated targeting on the Yin-yang dynamics of DNA methylation in disease and development. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.05.002
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Fig. 2. MiRNA-regulated epigenetic regulation between stem cell and cancer cell. The regulatory network between two epigenetic modifications (histone/DNA modifications and their corresponding catalytic proteins, PRC1/2 for histone modification; DNMTs, TETs and TDG for DNA methylation/demethylation circle) and three epi-miRNAs (miR-22, miR-26 and miR-29). The proved direct connections between different proteins are also shown.
Fig. 3. The proposed “Yin-Yang” model for genomic regulation of DNMT/TET/TDG mediated methylation/demethylation circle. DNA methylation patterns are dynamically balanced by methylation and demethylation processes. Transcriptional repression by DNA methylation (DNMTs) could lead to transcriptional remodeling at key anti-cancer genes. The promoter regions of these genes gain 5hmC and these changes ultimately lead to the aberrant methylation pattern seen in cancer. DNMTi, DNA methyltransferase inhibitor; MiRNAi, microRNA inhibitor; TETa, Ten-eleven translocation protein activator; TDGa, thymine-DNA glycosylase activator.
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cells (Pietersen et al., 2008). Delineating how these epigenetic pathways interact each other is a fundamental step toward the understanding of stem cell homeostasis and tumor initiation.
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MiR-26 cluster is another interesting epi-miRNA that associates with stem cells development and cancer progression through inactivation of DNA demethylation pathway. Previously, study has suggested miRNA-26 cooperate with other epigenetic regulator during osteogenic differentiation (Luzi et al., 2007), and inducing myogenesis via silencing the negative regulator of myogenesis EZH2 (Enhancer of Zeste Homolog 2, a key subunit of PRC2 complex) (Wong and Tellam, 2008). Recently, Fu XH et al. showed that miR-26a could directly target TETs and decrease 5hmC levels in pancreatic cells. miR-26a promotes pancreatic stem cell differentiation both in vitro and in vivo, which delineate a relation between miRNA, 5hmC and stem cell differentiation (Fu et al., 2013). In our
recent study, we also identified both miR-26a and miR-26b could repress Tet3 (the most abundant member of Tet family in testis) in spermatogonial stem cells, (SSCs) leading to reduced global 5hmC level (unpublished results). Stable expression of miR-26a and miR26b in SSCs promoted cellular differentiation. Taken together, these results highlight the promotion of pancreatic stem/progenitor cell differentiation and spermoatogenic progression through active epigenetic modulation induced by miR-26 cluster, which could be an alternative approach to increase the efficiency of pancreatic endocrine cells and sperm generation in vitro. Other than stem cell differentiation, miR-26 expression was reported to be repressed in various tumor types, which hints its potential role as a tumor-suppressor. MiR-26a was down-regulated in breast cancer specimens and cell lines (Zhang et al., 2011). It is required for initialization of apoptosis through endogenous and exogenous pathways through direct binding with EZH2. Importantly, EZH2 is the catalytic subunit of PRC2 complex, where it plays key role in PRC2-mediated histone modification, suggesting that miR-26 also could perform its role as an epigenetic regulator via modulating DNA methylation pathway and histone modification at the same time. Given the fact that Tet1 and PRC2 complex interacted in ESCs (Neri et al., 2013), it further confirming the possibility that miR-26 maybe functional as a dual epigenetic effector in ESCs via targeting Tet1 and PRC2 complex simultaneously.
3.3. MiR-29 cluster The most interesting point about miR-29 cluster is that it can target all three key enzymes (DNMTs, TETs and TDG) in DNA methylation/demethylation cycle. Previously, the miR-29 family were thought to suppress tumorigenesis by repressing de novo methylation. MiR-29 represses DNMT3A and DNMT3B expression in lung cancer tissues (Fabbri et al., 2007), and restores normal DNA methylation pattern in lung cancer cells via inducing of DNA methylation-silenced tumor suppressor genes, such as WWOX. These findings support a role of miR-29s in normalization of DNA methylation in Non-small cell lung cancer (NSCLC). While this idea was challenged until miR-29 was identified that could regulate other two key proteins in DNA demethylation pathway, TET and TDG (Zhang et al., 2013). Apart from the conventional role of “DNA methylation inhibitor”, miR-29 maybe also functional as an “extensive regulator” via regulation of all DNA modifications. MiR29 up-regulated the global DNA methylation level in some cancer
Please cite this article in press as: Tu J, et al. MicroRNAs mediated targeting on the Yin-yang dynamics of DNA methylation in disease and development. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.05.002
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cells and down-regulated DNA methylation in other cancer cells (Morita et al., 2013), suggesting that miR-29 modulates tumorigenesis by protecting against changes in the existing DNA methylation status rather than by preventing de novo methylation of DNA. Thus, just like miR-26 cluster, the role of miR-29 cluster in different tumors also depend on different targets. The role of miR-29 cluster in development has just began to emerge. We recently show ESC differentiation can be directed by non-coding RNA mediated epigenetic mechanism, which involves microRNA-29b (miR-29b) and Tet1. We also demonstrate miR29b/Tet1 regulatory axis contributes to mesendoderm lineage formation through Nodal signaling pathway by using in vitro and in vivo models. This novel regulatory axis also involves in repression of TDG, another important epigenetic regulator in active demethylation pathway. Our findings underscore the contribution of microRNA-mediated DNA demethylation dynamics and relate to key ectoderm and mesendoderm regulators during ESCs lineage specification. With this novel discovery, miR-29b could potentially be applied to enrich production of mesoderm and endoderm derivatives and be further differentiated into desired organ-specific cells. 4. Future prospects The discovery of active DNA demethylation pathway and the existence of microRNA modulation on the key regulators in DNA demethylation pathways have contributed significantly not only to an understanding of the molecular regulations but also provided new insights on epigenetic control during normal and disease development. Although global changes on DNA demethylation marks like 5hmC has been established in normal development and pathological states, its relationship with gene expression regulation remain elusive. There is a lot to be explored in the Yin-Yang cycle of DNA methylation, from how TETs divide their role in demethylation dynamics to how the subsequent modifications (5hmC, 5caC, 5fC) interact or get enriched with preferred genomic targets, chromatin remodeling complexes and epigenetic modifiers or modifications. With the advent of high-throughput genomic techniques like Oxidative Bisulfite Sequencing (OxBS-seq) (Booth et al., 2013) and TET-assisted Bisulfite Sequencing (TAB-seq) (Yu et al., 2012), DNA demethylation marks can be discriminated at single nucleotide resolution rapidly. Future studies are also required to elucidate the regulatory loop involving microRNAs and the epigenetic machinery, and investigate how to translate these findings into clinical applications. A better understanding of epigenetic regulatory mechanism of microRNA expression will help to elucidate the complex network of epigenetic modifications and design innovative strategies for regenerative medicine and cancer treatment. For example, the use of microRNAs or epigenetic editing (Chen et al., 2014) to either directly regulate gene expression, or to control the epigenetic machinery targeting the effector enzymes will create a promising perspective in biomedical sciences. References Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009;114(July (1)):144–7. Bartel DP. MicroRNAs: genomics, review biogenesis, mechanism, and function. Cell 2004;116(January (2)):281–97. Booth MJ, Ost TWB, Beraldi D, Bell NM, Branco MR, Reik W, et al. Oxidative bisulfite sequencing of 5-methylcytosine and 5-hydroxymethylcytosine. Nat Protoc 2013;8(September (10)):1841–51. Chen C-C, Wang K-Y, Shen C-KJ. The mammalian de novo DNA methyltransferases DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases. J Biol Chem 2012;287(September (40)):33116–21. Chen H, Kazemier HG, de Groote ML, Ruiters MHJ, Xu G-L, Rots MG. Induced DNA demethylation by targeting ten-eleven translocation 2 to the human ICAM-1
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Xu Y, Wu F, Tan L, Kong L, Xiong L, Deng J, et al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell 2011;42(May (4)):451–64. Yates LA, Norbury CJ, Gilbert RJC. The long and short of microRNA. Cell 2013; 153(April (3)):516–9. Yu M, Hon GC, Szulwach KE, Song C-X, Jin P, Ren B, et al. Tet-assisted bisulfite sequencing of 5-hydroxymethylcytosine. Nat Protoc 2012;7(November (2)):2159–70, Nature Publishing Group. Zhang B, Liu X-X, He J-R, Zhou C-X, Guo M, He M, et al. Pathologically decreased miR26a antagonizes apoptosis and facilitates carcinogenesis by targeting MTDH and EZH2 in breast cancer. Carcinogenesis 2011;32(January (1)):2–9, Oxford University Press. Zhang P, Huang B, Xu X, Sessa WC. Ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG), components of the demethylation pathway, are direct targets of miRNA-29a. Biochem Biophys Res Commun 2013;437(August (3)):368–73.
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