From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
insideblood
®
28 NOVEMBER 2013
I VOLUME 122, NUMBER 23
l l l RED CELLS, IRON, & ERYTHROPOIESIS
Comment on Hosoya et al, page 3798
The TRIMming on an erythroid repressor complex ----------------------------------------------------------------------------------------------------Margaret H. Baron1
1
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
In this issue of Blood, Hosoya et al identify a requirement for the corepressor Tripartite Motif Protein 28 (TRIM28) in erythroblast maturation.1
E
rythropoiesis produces billions of new red blood cells on a daily basis in our bone marrow. This process begins with the commitment of hematopoietic stem cells to a hierarchy of progenitors, including the common myeloid progenitor (CMP), the
megakaryocyte-erythrocyte progenitor (MEP), and the erythroid lineage-specific burstforming unit cells (early) and colony-forming unit cells (later). Colony-forming units mature through a tightly orchestrated developmental program in which hemoglobin
Cartoon showing possible repressor complexes formed through mutually exclusive recruitment of TRIM28, HDAC3, or the NuRD or CoREST complex by the DRED heterodimer of NR2C1 (formerly TR2) and NR2C2 (formerly TR4). The figure has been adapted with permission from Figure 8 in the article by Cui et al.5 Professional illustration by Debra T. Dartez.
BLOOD, 28 NOVEMBER 2013 x VOLUME 122, NUMBER 23
protein accumulates and organelles such as mitochondria and the nucleus are lost, resulting in the terminally differentiated erythrocytes that enter the bloodstream and transport oxygen to all tissues of the body.2 At different stages of ontogeny, hemoglobin is produced through the sequential expression or “switching” of distinct genes in the embryo, fetus, and adult.3 In the adult, embryonic/fetal b-like globin genes are repressed by transcription factors that include a DNA-binding heterodimer of the orphan nuclear receptors NR2C1 (TR2) and NR2C2 (TR4) (the DRED complex4) and an array of epigenetic regulatory cofactors5 (see figure). Hosoya et al1 used conditional gene ablation in adult mice to explore the function of the cofactor TRIM 28 (TRIM28 in humans, Trim28 in the mouse; also known as KRAB-associated protein 1 [KAP1], TIF1b, or KRIP-16) in hematopoiesis. TRIM28 is a ubiquitously expressed corepressor that is critical for early embryogenesis (the null mutation is embryonic lethal between embryonic days 5.5 and 8.5 in the mouse) and for the development of a variety of cell lineages, including B cells and T cells. It had not previously been studied in myeloid or erythroid cells. The authors expected to uncover a role for TRIM28 in repression of embryonic/fetal b-like globin genes in erythroid cells. Such a finding would have been of great clinical interest because induction of fetal hemoglobin F reduces the severity of symptoms in patients with sickle cell anemia, and repressors of the human fetal g-globin gene are potential targets for therapeutic intervention.3 However, to the authors’ surprise, the embryonic/fetal mouse b-like globin genes were not reactivated in adult red blood cells. Instead, the Trim28-deficient mice showed severe normocytic anemia, with disrupted maturation of erythroblasts. Defects in the numbers (increased) of CMPs and
3701
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
MEPs were also identified, suggesting an early function in myeloerythroid cell fate specification. Myelopoiesis was not affected in these mutants. Interestingly, Gata1 transcription was not affected by loss of Trim28, but the expression of genes encoding several other erythroid transcription factors and heme biosynthetic enzymes was reduced. Expression of apoptosis pathway genes was increased. In addition, as reported recently in another study, Trim28 mutant red cells failed to activate mitophagy-associated genes.7 Together, these observations indicate a crucial early role for Trim28 in erythroid development. One of the other monikers of TRIM28 is KAP1, from the ability of the protein to interact with Kru¨ ppel domain–containing zinc finger proteins. The founding member of the vertebrate erythroid Kr¨uppel-like zinc finger protein family, EKLF/KFL1, is a master regulator of erythropoiesis and can function as either a transcriptional activator or a repressor.8 It will be of interest to determine whether TRIM28 partners with EKLF/KFL1 during erythroid differentiation. In summary, TRIM28 has critical functions in at least 3 hematopoietic lineages. In maturing erythroblasts, TRIM28 regulates the expression of key transcription factors, heme biosynthetic enzymes, mitochondrial genes, and genes involved in cell survival. TRIM28 is generally considered a corepressor, and it is known to recruit repressors such as HP1 and SETDB1.6 However, coactivator functions have been reported.9,10 Interestingly, RNAseq analysis of 2 large populations of immature erythroblasts identified 1500 to 1600 genes that were downregulated in the Trim28-deficient cells.1 Additional work will be required to determine how many of these genes are direct targets of TRIM28-containing complexes and whether TRIM28 coactivates their expression or represses a repressor. TRIM28 has been implicated not only in transcriptional regulation but also in the maintenance of genome integrity, organization of chromatin structure, malignant transformation, and in control of retroelements.6 Whether TRIM28 regulates any of these processes in erythroid cells remains to be determined. Conflict-of-interest disclosure: The author declares no competing financial interests. n
3702
REFERENCES 1. Hosoya T, Clifford M, Losson R, Tanabe O, Engel JD. TRIM28 is essential for erythroblast differentiation in the mouse. Blood. 2013;122(23):3798-3807. 2. Hattangadi SM, Wong P, Zhang L, Flygare J, Lodish HF. From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood. 2011;118(24):6258-6268. 3. Sankaran VG, Xu J, Orkin SH. Advances in the understanding of haemoglobin switching. Br J Haematol. 2010;149(2):181-194. 4. Tanabe O, McPhee D, Kobayashi S, et al. Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4. EMBO J. 2007;26(9):2295-2306. 5. Cui S, Kolodziej KE, Obara N, et al. Nuclear receptors TR2 and TR4 recruit multiple epigenetic transcriptional corepressors that associate specifically with the embryonic b-type globin promoters in differentiated adult erythroid cells. Mol Cell Biol. 2011; 31(16):3298-3311.
6. Iyengar S, Farnham PJ. KAP1 protein: an enigmatic master regulator of the genome. J Biol Chem. 2011;286(30): 26267-26276. 7. Barde I, Rauwel B, Marin-Florez RM, et al. A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy. Science. 2013; 340(6130):350-353. 8. Siatecka M, Bieker JJ. The multifunctional role of EKLF/KLF1 during erythropoiesis. Blood. 2011;118(8): 2044-2054. 9. Rambaud J, Desroches J, Balsalobre A, Drouin J. TIF1beta/KAP-1 is a coactivator of the orphan nuclear receptor NGFI-B/Nur77. J Biol Chem. 2009;284(21): 14147-14156. 10. Maruyama A, Nishikawa K, Kawatani Y, et al. The novel Nrf2-interacting factor KAP1 regulates susceptibility to oxidative stress by promoting the Nrf2mediated cytoprotective response. Biochem J. 2011; 436(2):387-397. © 2013 by The American Society of Hematology
l l l LYMPHOID NEOPLASIA
Comment on Neven et al, page 3713
No immunosurveillance in human IL-10R deficiency ----------------------------------------------------------------------------------------------------Martin Oft1
1
ARMO BIOSCIENCES
In this issue of Blood, Neven et al report that a third of the patients with interleukin-10 receptor (IL-10R) deficiency develop B-cell lymphomas in the first decade of their life. The lymphomas uniformly contained amplifications of c-rel, activation of inflammatory nuclear factor kB (NF-kB) target genes, and a defective intratumoral CD81 T-cell tumor immunosurveillance.1
I
L-10 is an immune regulatory cytokine with anti-inflammatory properties but stimulatory functions on B cells and CD81 T cells. However, because of its antiinflammatory properties, IL-10 is frequently considered an immune-suppressive and tumor-promoting cytokine. To complicate the picture, IL-10 enhances the proliferation and survival of the differentiation, the expression of major histocompatibility complex class II (MHC II) molecules, immunoglobulins, and isotype switching in B cells. Therefore, IL-10 has been considered to promote the development of B-cell lymphomas.2 Two seemingly opposing functions in immune regulation were independently ascribed to IL-10 with its discovery in 1990, first B-cell–derived T-cell growth factor (B-TCGF),3 and secondly the cytokine synthesis inhibitory factor.4
As a B-TCGF, IL-10 induces the expression of CD3 and CD8 on adult thymocytes and consequently the proliferation of those cells. Further studies showed that IL-10 induced not only the proliferation but also the cytotoxicity of CD81 T cells. Treatment of mouse tumor models with recombinant human IL-10 or expression of IL-10 in tumor cells led to tumor inhibition and rejection, with CD81 T cells being essential for the tumor rejection. Genetic deficiency of IL-10 in mice (IL-102/2 mice) leads to inflammatory bowel disease (IBD) and to the development of colon carcinoma.5 Mice expressing elevated levels of IL-10 are resistant to tumor induction by carcinogens, with enhanced CD81 T-cell infiltration and expression of antigenpresenting molecules (MHC molecules) in the premalignant tissues.6 IL-10 directly induces cytotoxic effector molecules and interferon
BLOOD, 28 NOVEMBER 2013 x VOLUME 122, NUMBER 23
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2013 122: 3701-3702 doi:10.1182/blood-2013-10-531673
The TRIMming on an erythroid repressor complex Margaret H. Baron
Updated information and services can be found at: http://www.bloodjournal.org/content/122/23/3701.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
insideblood
®
28 NOVEMBER 2013
I VOLUME 122, NUMBER 23
l l l RED CELLS, IRON, & ERYTHROPOIESIS
Comment on Hosoya et al, page 3798
The TRIMming on an erythroid repressor complex ----------------------------------------------------------------------------------------------------Margaret H. Baron1
1
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
In this issue of Blood, Hosoya et al identify a requirement for the corepressor Tripartite Motif Protein 28 (TRIM28) in erythroblast maturation.1
E
rythropoiesis produces billions of new red blood cells on a daily basis in our bone marrow. This process begins with the commitment of hematopoietic stem cells to a hierarchy of progenitors, including the common myeloid progenitor (CMP), the
megakaryocyte-erythrocyte progenitor (MEP), and the erythroid lineage-specific burstforming unit cells (early) and colony-forming unit cells (later). Colony-forming units mature through a tightly orchestrated developmental program in which hemoglobin
Cartoon showing possible repressor complexes formed through mutually exclusive recruitment of TRIM28, HDAC3, or the NuRD or CoREST complex by the DRED heterodimer of NR2C1 (formerly TR2) and NR2C2 (formerly TR4). The figure has been adapted with permission from Figure 8 in the article by Cui et al.5 Professional illustration by Debra T. Dartez.
BLOOD, 28 NOVEMBER 2013 x VOLUME 122, NUMBER 23
protein accumulates and organelles such as mitochondria and the nucleus are lost, resulting in the terminally differentiated erythrocytes that enter the bloodstream and transport oxygen to all tissues of the body.2 At different stages of ontogeny, hemoglobin is produced through the sequential expression or “switching” of distinct genes in the embryo, fetus, and adult.3 In the adult, embryonic/fetal b-like globin genes are repressed by transcription factors that include a DNA-binding heterodimer of the orphan nuclear receptors NR2C1 (TR2) and NR2C2 (TR4) (the DRED complex4) and an array of epigenetic regulatory cofactors5 (see figure). Hosoya et al1 used conditional gene ablation in adult mice to explore the function of the cofactor TRIM 28 (TRIM28 in humans, Trim28 in the mouse; also known as KRAB-associated protein 1 [KAP1], TIF1b, or KRIP-16) in hematopoiesis. TRIM28 is a ubiquitously expressed corepressor that is critical for early embryogenesis (the null mutation is embryonic lethal between embryonic days 5.5 and 8.5 in the mouse) and for the development of a variety of cell lineages, including B cells and T cells. It had not previously been studied in myeloid or erythroid cells. The authors expected to uncover a role for TRIM28 in repression of embryonic/fetal b-like globin genes in erythroid cells. Such a finding would have been of great clinical interest because induction of fetal hemoglobin F reduces the severity of symptoms in patients with sickle cell anemia, and repressors of the human fetal g-globin gene are potential targets for therapeutic intervention.3 However, to the authors’ surprise, the embryonic/fetal mouse b-like globin genes were not reactivated in adult red blood cells. Instead, the Trim28-deficient mice showed severe normocytic anemia, with disrupted maturation of erythroblasts. Defects in the numbers (increased) of CMPs and
3701
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
MEPs were also identified, suggesting an early function in myeloerythroid cell fate specification. Myelopoiesis was not affected in these mutants. Interestingly, Gata1 transcription was not affected by loss of Trim28, but the expression of genes encoding several other erythroid transcription factors and heme biosynthetic enzymes was reduced. Expression of apoptosis pathway genes was increased. In addition, as reported recently in another study, Trim28 mutant red cells failed to activate mitophagy-associated genes.7 Together, these observations indicate a crucial early role for Trim28 in erythroid development. One of the other monikers of TRIM28 is KAP1, from the ability of the protein to interact with Kru¨ ppel domain–containing zinc finger proteins. The founding member of the vertebrate erythroid Kr¨uppel-like zinc finger protein family, EKLF/KFL1, is a master regulator of erythropoiesis and can function as either a transcriptional activator or a repressor.8 It will be of interest to determine whether TRIM28 partners with EKLF/KFL1 during erythroid differentiation. In summary, TRIM28 has critical functions in at least 3 hematopoietic lineages. In maturing erythroblasts, TRIM28 regulates the expression of key transcription factors, heme biosynthetic enzymes, mitochondrial genes, and genes involved in cell survival. TRIM28 is generally considered a corepressor, and it is known to recruit repressors such as HP1 and SETDB1.6 However, coactivator functions have been reported.9,10 Interestingly, RNAseq analysis of 2 large populations of immature erythroblasts identified 1500 to 1600 genes that were downregulated in the Trim28-deficient cells.1 Additional work will be required to determine how many of these genes are direct targets of TRIM28-containing complexes and whether TRIM28 coactivates their expression or represses a repressor. TRIM28 has been implicated not only in transcriptional regulation but also in the maintenance of genome integrity, organization of chromatin structure, malignant transformation, and in control of retroelements.6 Whether TRIM28 regulates any of these processes in erythroid cells remains to be determined. Conflict-of-interest disclosure: The author declares no competing financial interests. n
3702
REFERENCES 1. Hosoya T, Clifford M, Losson R, Tanabe O, Engel JD. TRIM28 is essential for erythroblast differentiation in the mouse. Blood. 2013;122(23):3798-3807. 2. Hattangadi SM, Wong P, Zhang L, Flygare J, Lodish HF. From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood. 2011;118(24):6258-6268. 3. Sankaran VG, Xu J, Orkin SH. Advances in the understanding of haemoglobin switching. Br J Haematol. 2010;149(2):181-194. 4. Tanabe O, McPhee D, Kobayashi S, et al. Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4. EMBO J. 2007;26(9):2295-2306. 5. Cui S, Kolodziej KE, Obara N, et al. Nuclear receptors TR2 and TR4 recruit multiple epigenetic transcriptional corepressors that associate specifically with the embryonic b-type globin promoters in differentiated adult erythroid cells. Mol Cell Biol. 2011; 31(16):3298-3311.
6. Iyengar S, Farnham PJ. KAP1 protein: an enigmatic master regulator of the genome. J Biol Chem. 2011;286(30): 26267-26276. 7. Barde I, Rauwel B, Marin-Florez RM, et al. A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy. Science. 2013; 340(6130):350-353. 8. Siatecka M, Bieker JJ. The multifunctional role of EKLF/KLF1 during erythropoiesis. Blood. 2011;118(8): 2044-2054. 9. Rambaud J, Desroches J, Balsalobre A, Drouin J. TIF1beta/KAP-1 is a coactivator of the orphan nuclear receptor NGFI-B/Nur77. J Biol Chem. 2009;284(21): 14147-14156. 10. Maruyama A, Nishikawa K, Kawatani Y, et al. The novel Nrf2-interacting factor KAP1 regulates susceptibility to oxidative stress by promoting the Nrf2mediated cytoprotective response. Biochem J. 2011; 436(2):387-397. © 2013 by The American Society of Hematology
l l l LYMPHOID NEOPLASIA
Comment on Neven et al, page 3713
No immunosurveillance in human IL-10R deficiency ----------------------------------------------------------------------------------------------------Martin Oft1
1
ARMO BIOSCIENCES
In this issue of Blood, Neven et al report that a third of the patients with interleukin-10 receptor (IL-10R) deficiency develop B-cell lymphomas in the first decade of their life. The lymphomas uniformly contained amplifications of c-rel, activation of inflammatory nuclear factor kB (NF-kB) target genes, and a defective intratumoral CD81 T-cell tumor immunosurveillance.1
I
L-10 is an immune regulatory cytokine with anti-inflammatory properties but stimulatory functions on B cells and CD81 T cells. However, because of its antiinflammatory properties, IL-10 is frequently considered an immune-suppressive and tumor-promoting cytokine. To complicate the picture, IL-10 enhances the proliferation and survival of the differentiation, the expression of major histocompatibility complex class II (MHC II) molecules, immunoglobulins, and isotype switching in B cells. Therefore, IL-10 has been considered to promote the development of B-cell lymphomas.2 Two seemingly opposing functions in immune regulation were independently ascribed to IL-10 with its discovery in 1990, first B-cell–derived T-cell growth factor (B-TCGF),3 and secondly the cytokine synthesis inhibitory factor.4
As a B-TCGF, IL-10 induces the expression of CD3 and CD8 on adult thymocytes and consequently the proliferation of those cells. Further studies showed that IL-10 induced not only the proliferation but also the cytotoxicity of CD81 T cells. Treatment of mouse tumor models with recombinant human IL-10 or expression of IL-10 in tumor cells led to tumor inhibition and rejection, with CD81 T cells being essential for the tumor rejection. Genetic deficiency of IL-10 in mice (IL-102/2 mice) leads to inflammatory bowel disease (IBD) and to the development of colon carcinoma.5 Mice expressing elevated levels of IL-10 are resistant to tumor induction by carcinogens, with enhanced CD81 T-cell infiltration and expression of antigenpresenting molecules (MHC molecules) in the premalignant tissues.6 IL-10 directly induces cytotoxic effector molecules and interferon
BLOOD, 28 NOVEMBER 2013 x VOLUME 122, NUMBER 23
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2013 122: 3701-3702 doi:10.1182/blood-2013-10-531673
The TRIMming on an erythroid repressor complex Margaret H. Baron
Updated information and services can be found at: http://www.bloodjournal.org/content/122/23/3701.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
