The Japanese Society of Developmental Biologists

Develop. Growth Differ. (2015) 57, 1–9

doi: 10.1111/dgd.12190

Review Article

Possible role of H1 histone in replication timing Reed A. Flickinger* Department of Biological Sciences, State University of New York at Buffalo, Buffalo, 14260 New York, USA

AT-rich repetitive DNA sequences become late replicating during cell differentiation. Replication timing is not correlated with LINE density in human cells (Ryba et al. 2010). However, short and properly spaced runs of oligo dA or dT present in nuclear matrix attachment regions (MARs) of the genome are good candidates for elements of AT-rich repetitive late replicating DNA. MAR attachment to the nuclear matrix is negatively regulated by chromatin binding of H1 histone, but this is counteracted by H1 phosphorylation, high mobility group proteins or, indirectly, core histone acetylation. Fewer MAR attachments correlates positively with longer average DNA loop size, longer replicons and an increase of late replicating DNA. Key words: AT-rich, DNA, H1 histone.

Introduction Restriction of alternative pathways of cell differentiation occurs during early embryonic development. Pluripotent embryonic stem cells express various tissuespecific genes at low levels prior to their choice of cell fate, i.e., cell determination (Efroni et al. 2008). Single cell derived multipotent adult progenitor cells, a subpopulation of mesenchyme stem cells, express a marker of pluripotency, Oct4, as well as genes specific for each of the three germ layers (Ji et al. 2008). Interestingly, both rat and human osteosarcoma cell lines also show markers of all three germ layers (Russinoff et al. 2011). The restriction of expression of tissue-specific genes for alternative phenotypes as pluripotent cells differentiate may result from their becoming late replicating. Late replication may occur because of restriction of early replication of these sequences (Rhind & Gilbert 2013). Mouse embryonic stem cells contain considerably less H1 histone than differentiated mouse cells (Woodcock et al. 2006). There is an increase of late replicating DNA during embryonic stem cell differentiation (Hiratani et al. 2008). The present paper presents

*Author to whom all correspondence should be addressed. Email: [email protected] Received 27 August 2014; revised 3 November 2014; accepted 4 November 2014. © 2014 The Author Development, Growth & Differentiation © 2014 Japanese Society of Developmental Biologists

evidence that this restriction may involve the relative amounts of chromatin-bound dephosphorylated H1 histone relative to that of one or more of the high mobility group (HMG) chromatin proteins. H1 histone binding to chromatin is reduced by H1 phosphorylation and, indirectly, by acetylation of the core histones.

Early work: AT-rich DNA becomes late replicating in developing frog embryos Autoradiography and quantitative determinations of labeled DNA synthesis in partially synchronized explants from early frog embryos showed an increase of late replicating DNA during early development (Remington & Flickinger 1971). Subsequent work indicated a shift of labeled thymidine, but not deoxyguanosine, incorporation into late replicating DNA during this period (Remington & Flickinger 1978). Isolated nuclei in an in vitro system displayed a significant increase of labeled thymidine triphosphate (TTP), but not dCTP, incorporation into late replicating DNA during early development, (Table 1), (Flickinger & Richman 1983). These results indicate that AT-rich sequences become late replicating. The base composition of poly (A+) nuclear RNA was about 15% less AU enriched for later stage embryos, which have an increased level of late replicating ATrich DNA, than for earlier stage frog embryos with less late replicating DNA (Pine & Flickinger 1987). Frog embryo poly (A+) nuclear RNA was hybridized to filter-bound DNA with and without RNase treatment of the filters. The first procedure detects only repetitive


R. A. Flickinger

Table 1. Incorporation of labeled deoxynucleotide triphosphates into early and late replicating DNA of isolated nuclei of Rana embryos Early neurulae cpm/lg DNA Hours after release from 5-FUdR inhibition 2 h (early S) 6 h (late S)

Early tailbuds cpm/lg DNA







326 201

162 111

2.01 1.81

213 133

239 271

0.89 0.49

From Flickinger & Richman (1983).

transcripts; omission of RNase treatment detects hybridized repetitive plus contiguous covalently bound single copy DNA transcripts. Base composition determinations showed that the repetitive transcripts were about 7% enriched with AU, as compared to the contiguous and interspersed single copy transcripts (Pine & Flickinger 1987). This shows the transcription of ATrich repetitive sequences. Filter hybridizations with frog embryo nuclear RNA showed both a qualitative and quantitative restriction of transcription of repetitive DNA sequences during early development of the frog embryo (Daniel & Flickinger 1971). These results suggest that an increase of late replication of AT-rich and repetitive DNA sequences restricts transcription from AT-rich repetitive sequences during early development of frog embryos.

formation and arrangement of nucleosomes and these sequences are present in numerous yeast promoters (Iyer & Struhl 1995; Suter et al. 2000). Regions of the genome that bind the nuclear matrix are called matrix attachment regions (MARs) and contain short (~10 bp) stretches of A or T (Gasser & Laemmli 1986). The AT-richness of genome sequences tends to deplete nucleosomes (Nelson 1987; Kaplan chali 2013). G-rich et al. 2009; Leonard & Me sequences also may disfavor nucleosome formation chali 2013). (Leonard & Me Both H1 histone (Cui & Zhurkin 2009) and each of the HMG proteins (Catez et al. 2004) preferentially bind the same AT-rich sequences in chromatin. H1 histones also prevents AT-rich MARs from attaching to the nuclear matrix in an in vitro system (Zhao et al. 1993). HMGA counteracts this effect of H1 histone.

Depletion of nucleosomes at replicon origins Replication initiation is favored by the open chromatin configurations of CpG islands, characteristic of housekeeping genes (Delgado et al. 1998). These genes mostly replicate early. The changes of replication timing in frog embryos (Flickinger 2001) and mouse embryonic stem cells (Hiratani et al. 2008) during cell differentiation occurs for AT-rich sequences, not those that are GC-rich. Prereplication complexes preferentially bind genomic regions with fewer nucleosomes (Lubelsky et al. 2011). CpG islands have a reduced nucleosome content which would account for the early replication of housekeeping genes. In fission yeast, S. pombe, the origin recognition complex (ORC) binds to short (four to six nucleotides) asymmetric AT tracts (A and T on separate DNA strands) that are spaced four to eight nucleotides apart (Dai et al. 2005). A greater number of asymmetric AT tracts, together with their proper spacing, increased the binding of ORC to chromatin DNA. Origin recognition complex preferentially binds asymmetric stretches of A and T (DePamphilis 2005). In bacteriophage lambda DNA replicating in a Xenopus egg extract clusters of replicon origins preferentially are activated at asymmetric AT islands (Stanojcic et al. 2008). In yeast poly (dAdT) interferes with the

Replication initiating factors and timing of replication In fission yeast ORC binding is delayed for late firing replicon origins (Wu & Nurse 2009). They propose that a limited amount of ORC causes this delay and results in late replication. Extending mitosis time allowed more equal ORC binding and some late firing origins underwent earlier activation. Subsequent work with yeast showed that overexpression of various replication initiation factors cause some late firing replicon origins to initiate early (Mantiero et al. 2011; Tanaka et al. 2011). Depletion of H1 histone from chromatin allows more replication factor binding (Lu et al. 1998). This is consistent with greater binding of H1 causing delayed replicon initiation.

Histone acetylation and replication timing Experimental induction of acetylation of H3 and H4 core histones causes some late replicating DNA sequences to replicate earlier (Vogelauer et al. 2002; Aparicio et al. 2004; Goren et al. 2008). Mammalian fibroblasts treated with trichostatin (TSA), an inhibitor of histone deacetylase, increased replicon origin numbers at the adenosine monophosphate deaminase 2 locus

© 2014 The Author Development, Growth & Differentiation © 2014 Japanese Society of Developmental Biologists

AT-rich repetitive late replicating DNA

(Gay et al. 2010). TSA increased acetylation of the core histones, but also reduced the pool size of dTTP and dCTP, which decreased the rate of replicon fork progression. Slowing fork elongation is known to activate additional replicons (Anglana et al. 2003). Gay et al. (2010) found that provision of thymidine and cytidine to TSA-treated cells abrogated the increase of replicon numbers, even though core histone acetylation increased due to TSA. Fork speed was not diminished by TSA when excess thymidine and cytidine were present. They conclude that the size of the dNTP pool, not core histone acetylation, regulates the number of replicon origins activated. Any effect of core histone acetylation on replication timing may also involve H1 histone. TSA inhibition of core histone deacytylation decreased the binding time of green fluorescent protein tagged H1° and H1c linked histones to chromatin (Mistelli et al. 2000). Inhibition of deacetylation of newly synthesized core histone H4 by butyrate caused H1 histone depletion in nascent chromatin (Perry & Annunziato 1991). These results indicate not core histone acetylation causes reduced H1 binding to chromatin, perhaps accounting for the increase of early replicating DNA (Vogelauer et al. 2002; Aparicio et al. 2004; Goren et al. 2008).


change the DNA loop size or replicon number. The mitotic egg extract contains the histone chaperone nucleoplasmin which removes H1 and H1° from the erythrocyte chromatin, thus increasing the frequency of replicon initiation (Lu et al. 1999). This suggests that H1 histone level affects replication timing. Nucleoplasmin removes the linker histones and increases replicon initiation. This is consistent with additional H1 delaying initiation. H1 histone binding to metaphase chromosomes is much weaker than to interphase chromatin (Wu et al. 1986; Bordignon et al. 2001; Loberg & Rundquist 2006; Green et al. 2010). Most H1 histone is translocated from metaphase chromosomes to the cytoplasm before its relocation to chromatin at telophase and early G1 phase (Fig. 1) (Bleher & Martin

Nuclear matrix attachment regions and replicon origins Matrix attachment regions consist of short interspersed stretches of oligo dA and/or oligo dT sequences that bind the nuclear matrix, an insoluble proteinaceous intranuclear framework (Gasser & Laemmli 1986). Most MARs are 300–4000 bp long and are believed to be remnants of transposable elements (Jordan et al. 2003). An increase in the number of A or T tracts, properly spaced, increased the binding affinity of MARs for the nuclear matrix (Roque et al. 2004). Fewer MARs attached to the nuclear matrix decreases the number of DNA loops and increases their average length. The size of DNA loops correlates positively with the replicon length in various plants and animals (Buongiorno-Nardelli et al. 1982). Sites of MAR attachment to the nuclear matrix colocalize with replicon origins (Razin et al. 1991; Lagarkova et al. 1998; Girard-Reydet et al. 2004; Anachova et al. 2005; Radichev et al. 2005). Erythrocyte nuclei of Xenopus have DNA loops averaging 97 kb in length. When these nuclei were incubated with a mitotic stage extract from Xenopus eggs, loop size decreased to 15 kb (Lemaitre et al. 2005). In the subsequent S phase of erythrocyte nuclei in mitotic egg extract there was a large increase in the number of activated replicon origins. Incubation of erythrocyte nuclei in an S phase extract of Xenopus eggs did not

Fig. 1. Density of staining with antibodies to dephosphorylated and phosphorylated H1 histone in chromatin (top panel) and cytoplasm (bottom panel) during the HeLa cell cycle (Bleher & Martin 1999). , H1; , H1P.

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R. A. Flickinger

1999). This temporary loss of much of the bound H1 histone from metaphase chromosomes may account for the increased number of MARs attaching to the nuclear matrix and creation of additional replicon origins in Xenopus erythrocyte nuclei incubated in a Xenopus mitotic egg extract (Lemaitre et al. 2005). Addition of adenine plus uridine to the medium accelerates replicon fork speed of mammalian cells and doubles average DNA loop size in the subsequent G1 phase (Courbet et al. 2008). Slowing fork progression with hydroxyurea, an inhibitor of ribonucleoside diphosphate reductase, reduces dNTP pool size and decreases average DNA loop size in the subsequent G1 phase and increases replicon number. They suggest that the rate of replicon fork elongation sets chromatin loop size and origin choice in cultured mammalian cells (Anglana et al. 2003; Courbet et al. 2008). Replicon origin sequences showed a random distribution between matrix-attached DNA and loop DNA (Djeliova et al. 2001a). This may result from origins moving away from the nucleus matrix during DNA replication (Courbet et al. 2008). In CHO cells replicon origins associate with the nuclear matrix in late G1 phase, not in early G1 phase (Djeliova et al. 2001b). Replication timing in this cell line is established in early G1 phase (Dimitrova & Gilbert 1999). On possible explanation for this difference is that the number of origins activated during S phase is much less than the number of potential origin initiation sites (Lebofsky et al. 2006). The time of replicon origin association with the nuclear matrix (late G1) (Djeliova et al. 2001b) better corresponds to the time at which selection of origins to be used in the subsequent S phase occurs (Li et al. 2003). During early development of amphibian embryos there is an increase of DNA loop size, as well as that of replicons (Fig. 2) (Grabar & Flickinger 1981; Buongiorno-Nardelli et al. 1982; Flickinger et al. 1986). There is an increase in the amount of late replicating DNA during this period (Flickinger 2001). The positive correlation between DNA loop size, replicon length and the relative quantity of late replicating DNA occurs in different regions of the early tailbud embryos of Rana as well. Belly endoderm cells have more late replicating DNA (Remington & Flickinger 1971) and larger DNA loops (Flickinger et al. 1986) than do dorsal axial cells.

H1 histone and replication timing Addition of somatic H1 histone to a Xenopus egg extract containing sperm nuclei reduced the frequency

of replicon initiation in the sperm DNA (Lu et al. 1998). Neither the egg extract nor the sperm nuclei contained endogenous somatic H1 histone. Knockdown of the H1 histone with small interfering RNAs in the slime mold Physarum shifted some late replicating DNA to earlier replication (Thiriet & Hayes 2009). A triple knockout of H1c, H1e and H1° linker histones in mice led to a decrease of facultative heterochromatin in rod photoreceptor cells (Popova et al. 2013). Facultative heterochromatin often is enriched with repetitive AT-rich sequences and is late replicating, e.g., the inactive mammalian X chromosome (Bailey et al. 2000) and H1 histone preferentially binds ATrich sequences in chromatin (Cui & Zhurkin 2009). This suggests a role for H1 in inducing late replication of AT-rich repetitive DNA sequences. Phosphorylation of H1 histone is believed to lead to its transitory removal from its binding to chromatin (Dou et al. 1999). Inhibition of dephosphorylation of H1 histone with inhibitors of protein phosphatases in Physarum increased the relative proportion of early replicating DNA (Thiriet & Hayes 2009). Cyclin A-Cdk1 activity phosphorylates H1 histone. Ectopic expression of cyclin A-Cdk1 in mouse embryonic fibroblasts caused some late firing replicon origins to be activated in early S phase (Katsuno et al. 2009). The addition of cyclin A to mammalian cell nuclei in Xenopus egg extract increased the number of replicon clusters but had little effect on replication timing (Thomson et al. 2010). The discrepancy between the results of Katsuno et al. (2009) and Thomson et al. (2010) may be that the former group overexpressed cyclin A-Cdk1 in mouse fibroblasts and Thomson et al. (2010) used the in vitro Xenopus egg extract. On would predict nearmaximal origin activations in the egg extract. Addition of cyclin A in this egg extract system is unlikely to affect replication timing since initiation is already maximal. There is more chromatin-bound dephosphorylated H1 histone in late S than in early S phase of mammalian cells (Fig. 1) (Bleher & Martin 1999; Happel et al. 2009). Since H1 histone preferentially binds AT-rich chromatin DNA sequences (Cui & Zhurkin 2009), it is reasonable to suggest that binding of dephosphorylated H1 histone to AT-rich replicon origin initiation sites may delay their firing, thus accounting for their late replication. The determinant of replication timing (RTD) is lost at the replication fork during S phase and is not present in G2 phase cells (Lu et al. 2010). Phosphorylation of H1 histones occurs at the site of DNA replication (Alexandrow & Hamlin 2005). Also there is a high level of H1 phosphorylation in G2 phase cells (Talasz et al. 1996). The RTD is present in quiescent cells (Lu et al.

© 2014 The Author Development, Growth & Differentiation © 2014 Japanese Society of Developmental Biologists

AT-rich repetitive late replicating DNA


Gastrula endoderm Av. 33.4 μ 15




Neurula endoderm Av. 49.2 μ



Tailbud endoderm Av. 77.3 μ 10


Fig. 2. Frequency distribution of replicon sizes for endoderm cells of gastrulae, neurulae and tailbuds of Rana pipiens (Grabar & Flickinger 1981).












Interval between neighboring initiation points (μ)

2010), known to have a low level of H1 phosphorylation. H1 phosphorylation allows the transient release of H1 from chromatin (Bleher & Martin 1999; Dou et al. 1999; Lever et al. 2000). Maximal binding of dephosphorylated H1 histone to chromatin is at early G1 phase (Fig. 1) (Bleher & Martin 1999). This is the time at which replication timing is established (Dimitrova & Gilbert 1999). The loss of the RTD during S phase (Lu et al. 2010) coincides with an increase of cytoplasmic phosphorylated H1 histone (Fig. 1) (Bleher & Martin 1999). The data reviewed suggest chromatin-bound dephosphoryated H1 histone delays or prevents initiation of replication. Direct evidence for a role of H1 histone in replication timing is observed in Physarum and mouse embryo fibroblasts. In Physarum reducing the amount of H1 or maintaining H1 phosphorylation increases the extent of

earlier replication (Thiriet & Hayes 2009). In the fibroblasts increasing H1 phosphorylation promotes earlier replication (Katsuno et al. 2009).

High mobility group chromatin proteins and replication timing H1 histone and each of the HMG proteins (A, B, N) compete for the same chromatin binding sites (Catez et al. 2004). If H1 histone delayed replicon origin activation, then this effect may be counteracted by one or more of the HMG proteins. An interaction between ORC and HMGA1a targets ORC to replicon origins (Thomae et al. 2008). DNA replication initiates at or near HMGA1a-enriched sites in chromatin when HMGA1a was targeted to sites on a plasmid DNA. This recruited ORC to those sites and created artificial

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R. A. Flickinger

Tailbud dorsal axial region 25 Early S phase Late S phase


20 15 10 5 0 0.1



0.6 0.4 0.5 Growth rate (µ/min)


replicon origins. These data suggest that chromatin binding of one or more of the HMG proteins would prevent or reduce the effect of H1 histone in delaying replicon initiation.

Replicons, replicon clusters and late replicating DNA Replicon length increases during early development of Rana embryos (Fig. 2), while the rate of replicon fork elongation increases during late S phase (Fig. 3) (Grabar & Flickinger 1981). During differentiation of mouse embryonic stem cells there is an increase of replicon cluster size, but there are fewer clusters (Hiratani et al. 2008). The size of replicon clusters ranges from 0.2 to 2 Mbp (Hiratani et al. 2008), but most are about 1 Mbp and contain three to six individual replicons (Liapunova 1994; Ma et al. 1998). Some clusters or foci may contain one long replicon (Berezney et al. 2000). Although different replicon clusters are activated at different times during S phase, origins within each cluster fire more or less simultaneously (Berezney et al. 2000). This may be due to their similar base composition (Comings 1972). There are fewer and longer replicon clusters in late replicating DNA than in early replicating DNA (Painter & Schaefer 1971; Berezney et al. 2000; Sadoni et al. 2004; Labit et al. 2008; Ryba et al. 2010). The larger replicon clusters in late replicating DNA contain fewer individual replicons than the smaller clusters firing in early S phase (Goldar et al. 2009; Yang et al. 2010; Cayrou et al. 2011). This indicates a longer average length for individual replicons in the larger clusters in late replicating DNA. The rate of replicon fork elongation is more rapid for late replicating DNA, as compared to DNA replicating



Fig. 3. Replicon fork growth rates of dorsal axial cells of early tailbuds of Rana pipiens during early and late S phase (Grabar & Flickinger 1981).

early (Fig. 3) (Painter & Schaefer 1971; Housman & Huberman 1975; Grabar & Flickinger 1981; Malinsky et al. 2000; Takebayashi et al. 2005). Guilbaud et al. (2011) found no change of replications fork speed during S phase in HeLa cells. They attribute the earlier results to an increased synchrony of replicon activation in late replicating DNA. There is an increase in the rate of DNA replication as mammalian cells progress through S phase, although there is a slight decrease at very late S phase (Woodfine et al. 2004). This increase appears due to more rapid fork elongation during late S phase. There is an inverse relation between replicon fork speed and the number of activated replicon origins (Zhong et al. 2013). Increasing the pool size of dNTPs increases replicon fork speed in early, but not in late replicating DNA (Malinsky et al. 2000). As noted previously, the addition of adenine plus uridine to cultured cells doubles their rate of fork elongation and the size of DNA loops in the subsequent G1 phase (Courbet et al. 2008). It also decreased the number of activated replicon origins. Both a larger average DNA loop size and longer replicons characterize late replicating DNA. If late replication has a role in cell differentiation, then an experimental means of inducing late replication might be beneficial. The results reviewed suggest that experimentally increasing replicon fork elongation rate might be a productive approach.

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R. A. Flickinger

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AT-rich repetitive late replicating DNA

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Possible role of H1 histone in replication timing.

AT-rich repetitive DNA sequences become late replicating during cell differentiation. Replication timing is not correlated with LINE density in human ...
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