The Experts below are selected from a list of 1884 Experts worldwide ranked by ideXlab platform
Xin Yang - One of the best experts on this subject based on the ideXlab platform.
-
Unique Structural Platforms of Suz12 Dictate Distinct Classes of PRC2 for Chromatin Binding.
Molecular Cell, 2018Co-Authors: Siming Chen, Lianying Jiao, Murtada Shubbar, Xin YangAbstract:Summary Developmentally regulated accessory subunits dictate PRC2 function. Here, we report the crystal structures of a 120 kDa heterotetrameric complex consisting of Suz12, Rbbp4, JARID2, and Aebp2 fragments that is minimally active in nucleosome binding and of an inactive binary complex of Suz12 and Rbbp4. Suz12 contains two unique structural platforms that define distinct classes of PRC2 holo complexes for chromatin binding. Aebp2 and Phf19 compete for binding of a non-canonical C2 domain of Suz12; JARID2 and EPOP occupy an overlapped Suz12 surface required for chromatin association of PRC2. Suz12 and Aebp2 progressively block histone H3K4 binding to Rbbp4, suggesting that Rbbp4 may not be directly involved in PRC2 inhibition by the active H3K4me3 histone mark. Nucleosome binding enabled by JARID2 and Aebp2 is in part accounted for by the structures, which also reveal that disruption of the JARID2-Suz12 interaction may underlie the disease mechanism of an oncogenic chromosomal translocation of Suz12.
-
Unique Structural Platforms of Suz12 Dictate Distinct Classes of PRC2 for Chromatin Binding.
Molecular Cell, 2018Co-Authors: Siming Chen, Lianying Jiao, Murtada Shubbar, Xin YangAbstract:Summary Developmentally regulated accessory subunits dictate PRC2 function. Here, we report the crystal structures of a 120 kDa heterotetrameric complex consisting of Suz12, Rbbp4, JARID2, and Aebp2 fragments that is minimally active in nucleosome binding and of an inactive binary complex of Suz12 and Rbbp4. Suz12 contains two unique structural platforms that define distinct classes of PRC2 holo complexes for chromatin binding. Aebp2 and Phf19 compete for binding of a non-canonical C2 domain of Suz12; JARID2 and EPOP occupy an overlapped Suz12 surface required for chromatin association of PRC2. Suz12 and Aebp2 progressively block histone H3K4 binding to Rbbp4, suggesting that Rbbp4 may not be directly involved in PRC2 inhibition by the active H3K4me3 histone mark. Nucleosome binding enabled by JARID2 and Aebp2 is in part accounted for by the structures, which also reveal that disruption of the JARID2-Suz12 interaction may underlie the disease mechanism of an oncogenic chromosomal translocation of Suz12.
Youngsook Lee - One of the best experts on this subject based on the ideXlab platform.
-
myocardial specific ablation of jumonji and at rich interaction domain containing 2 JARID2 leads to dilated cardiomyopathy in mice
Journal of Biological Chemistry, 2019Co-Authors: Eunjin Cho, Hyunjun Kang, Dae-ki Kang, Youngsook LeeAbstract:Cardiomyopathy is a common myocardial disease that can lead to sudden death. However, molecular mechanisms underlying cardiomyopathy remain unclear. Jumonji and AT-rich interaction domain–containing 2 (JARID2) is necessary for embryonic heart development, but functions of JARID2 after birth remain to be elucidated. Here, we report that myocardial-specific deletion of JARID2 using αMHC::Cre mice (JARID2αMHC) causes dilated cardiomyopathy (DCM) and premature death 6–9 months after birth. To determine functions of JARID2 in the adult heart and DCM, we analyzed gene expression in the heart at postnatal day (p)10 (neonatal) and 7 months (DCM). Pathway analyses revealed that dysregulated genes in JARID2αMHC hearts at p10, prior to cardiomyopathy, represented heart development and muscle contraction pathways. At 7 months, down-regulated genes in JARID2αMHC hearts were enriched in metabolic process and ion channel activity pathways and up-regulated genes in extracellular matrix components. In normal hearts, expression levels of contractile genes were increased from p10 to 7 months but were not sufficiently increased in JARID2αMHC hearts. Moreover, JARID2 was also necessary to repress fetal contractile genes such as TroponinI1, slow skeletal type (Tnni1) and Actin alpha 2, smooth muscle (Acta2) in neonatal stages through ErbB2-receptor tyrosine kinase 4 (ErbB4) signaling. Interestingly, Ankyrin repeat domain 1 (Ankrd1) and Neuregulin 1 (Nrg1), whose expression levels are known to be increased in the failing heart, were already elevated in JARID2αMHC hearts within 1 month of birth. Thus, we demonstrate that ablation of JARID2 in cardiomyocytes results in DCM and suggest that JARID2 plays important roles in cardiomyocyte maturation during neonatal stages.
-
Myocardial-specific ablation of Jumonji and AT-rich interaction domain–containing 2 (JARID2) leads to dilated cardiomyopathy in mice
The Journal of biological chemistry, 2019Co-Authors: Eunjin Cho, Hyunjun Kang, Dae-ki Kang, Youngsook LeeAbstract:Cardiomyopathy is a common myocardial disease that can lead to sudden death. However, molecular mechanisms underlying cardiomyopathy remain unclear. Jumonji and AT-rich interaction domain–containing 2 (JARID2) is necessary for embryonic heart development, but functions of JARID2 after birth remain to be elucidated. Here, we report that myocardial-specific deletion of JARID2 using αMHC::Cre mice (JARID2αMHC) causes dilated cardiomyopathy (DCM) and premature death 6–9 months after birth. To determine functions of JARID2 in the adult heart and DCM, we analyzed gene expression in the heart at postnatal day (p)10 (neonatal) and 7 months (DCM). Pathway analyses revealed that dysregulated genes in JARID2αMHC hearts at p10, prior to cardiomyopathy, represented heart development and muscle contraction pathways. At 7 months, down-regulated genes in JARID2αMHC hearts were enriched in metabolic process and ion channel activity pathways and up-regulated genes in extracellular matrix components. In normal hearts, expression levels of contractile genes were increased from p10 to 7 months but were not sufficiently increased in JARID2αMHC hearts. Moreover, JARID2 was also necessary to repress fetal contractile genes such as TroponinI1, slow skeletal type (Tnni1) and Actin alpha 2, smooth muscle (Acta2) in neonatal stages through ErbB2-receptor tyrosine kinase 4 (ErbB4) signaling. Interestingly, Ankyrin repeat domain 1 (Ankrd1) and Neuregulin 1 (Nrg1), whose expression levels are known to be increased in the failing heart, were already elevated in JARID2αMHC hearts within 1 month of birth. Thus, we demonstrate that ablation of JARID2 in cardiomyocytes results in DCM and suggest that JARID2 plays important roles in cardiomyocyte maturation during neonatal stages.
-
Cardiac-specific developmental and epigenetic functions of JARID2 during embryonic development.
The Journal of biological chemistry, 2018Co-Authors: Eunjin Cho, Clayton D. Carlson, Mattew R Mysliwiec, Assem Z Ansari, Robert J. Schwartz, Youngsook LeeAbstract:Epigenetic regulation is critical in normal cardiac development. We have demonstrated that the deletion of JARID2 (Jumonji (Jmj) A/T-rich interaction domain 2) in mice results in cardiac malformations recapitulating human congenital cardiac disease and dysregulation of gene expression. However, the precise developmental and epigenetic functions of JARID2 within the developing heart remain to be elucidated. Here, we determined the cardiac-specific functions of JARID2 and the genetic networks regulated by JARID2. JARID2 was deleted using different cardiac-specific Cre mice. The deletion of JARID2 by Nkx2.5-Cre mice (JARID2Nkx) caused cardiac malformations including ventricular septal defects, thin myocardium, hypertrabeculation, and neonatal lethality. JARID2Nkx mice exhibited elevated expression of neural genes, cardiac jelly, and other key factors including Isl1 and Bmp10 in the developing heart. By employing combinatorial genome-wide approaches and molecular analyses, we showed that JARID2 in the myocardium regulates a subset of JARID2 target gene expression and H3K27me3 enrichment during heart development. Specifically, JARID2 was required for PRC2 occupancy and H3K27me3 at the Isl1 promoter locus, leading to the proper repression of Isl1 expression. In contrast, JARID2 deletion in differentiated cardiomyocytes by cTnt-Cre mice caused no gross morphological defects or neonatal lethality. Thus, the early deletion of JARID2 in cardiac progenitors, prior to the differentiation of cardiac progenitors into cardiomyocytes, results in morphogenetic defects manifested later in development. Our studies reveal that there is a critical window during early cardiac progenitor differentiation when JARID2 is crucial to establish the epigenetic landscape at later stages of development.
-
Late-stage differentiation of embryonic pancreatic β-cells requires JARID2.
Scientific reports, 2017Co-Authors: Sara Cervantes, Youngsook Lee, Marta Fontcuberta-pisunyer, Joan-marc Servitja, Rebeca Fernandez-ruiz, Ainhoa Garcia, Lidia Martínez Sánchez, Ramon Gomis, Rosa GasaAbstract:JARID2 is a component of the Polycomb Repressor complex 2 (PRC2), which is responsible for genome-wide H3K27me3 deposition, in embryonic stem cells. However, JARID2 has also been shown to exert pleiotropic PRC2-independent actions during embryogenesis. Here, we have investigated the role of JARID2 during pancreas development. Conditional ablation of JARID2 in pancreatic progenitors results in reduced endocrine cell area at birth due to impaired endocrine cell differentiation and reduced prenatal proliferation. Inactivation of JARID2 in endocrine progenitors demonstrates that JARID2 functions after endocrine specification. Furthermore, genome-wide expression analysis reveals that JARID2 is required for the complete activation of the insulin-producing β-cell differentiation program. JARID2-deficient pancreases exhibit impaired deposition of RNAPII-Ser5P, the initiating form of RNAPII, but no changes in H3K27me3, at the promoters of affected endocrine genes. Thus, our study identifies JARID2 as a fine-tuner of gene expression during late stages of pancreatic endocrine cell development. These findings are relevant for generation of transplantable stem cell-derived β-cells.
-
Increased nuchal translucency origins from abnormal lymphatic development and is independent of the presence of a cardiac defect.
Prenatal diagnosis, 2015Co-Authors: Nicole B. Burger, Youngsook Lee, Mireille N. Bekker, Evelien Kok, Christianne J.m. De Groot, James F. Martin, Weinian Shou, Peter J. Scambler, Vincent M. Christoffels, Monique C. HaakAbstract:Objective To assess whether cardiac failure, because of cardiac defects, and abnormal jugular lymphatic development are involved in nuchal edema (NE) – the morphological equivalent of increased nuchal translucency – in various euploid mutant mouse models. Method Mouse embryos with lymphatic abnormalities and NE (Ccbe1−/−), with cardiac defects and NE (Fkbp12−/−, Tbx1−/−, Chd7fl/fl;Mesp1Cre, JARID2−/−NE+) and with cardiac malformations without NE (Tbx2−/−, Pitx2−/−, Fgf10−/−, JARID2−/−NE−) were examined. Embryos were analyzed from embryonic day 11.5 to 15.5. Markers for lymphatic vessels, endothelium, smooth muscle cells and nerves were used to study the nuchal region. Hematoxylin–Azophloxine staining was performed to examine cardiac morphology. Results Mouse embryos with lymphatic abnormalities and NE (Ccbe1−/−) showed no formation of the jugular lymphatic sac but normal cardiac morphology. In mouse embryos with cardiac defects and NE (Fkbp12−/−, Tbx1−/−, Chd7fl/fl;Mesp1Cre, JARID2−/−NE+) enlarged jugular lymphatic sacs or large nuchal cavities within the NE were found. In mouse embryos with a cardiac malformation without NE (Tbx2−/−, Pitx2−/−, Fgf10−/−, JARID2−/−NE−) normal jugular lymphatic sacs were observed. Conclusion NE consistently coincides with abnormal jugular lymphatic development in euploid mouse embryos, independent of cardiac anatomy. NE is unlikely to be caused by temporary cardiac failure solely because of a cardiac defect. © 2015 John Wiley & Sons, Ltd.
Judith Davie - One of the best experts on this subject based on the ideXlab platform.
-
JARID2 and the prc2 complex regulate the cell cycle in skeletal muscle
Journal of Biological Chemistry, 2019Co-Authors: Abhinav Adhikari, Pramish Mainali, Judith DavieAbstract:JARID2 is a noncatalytic member of the polycomb repressive complex 2 (PRC2) which methylates of histone 3 lysine 27 (H3K27). In this work, we show that JARID2 and the PRC2 complex regulate the cell cycle in skeletal muscle cells to control proliferation and mitotic exit. We found that the stable depletion of JARID2 leads to increased proliferation and cell accumulation in S phase. The regulation of the cell cycle by JARID2 is mediated by direct repression of both cyclin D1 and cyclin E1, both of which are targets of PRC2-mediated H3K27 methylation. Intriguingly, we also find that the retinoblastoma protein (RB1) is a direct target of JARID2 and the PRC2 complex. The depletion of JARID2 is not sufficient to activate RB1. However, the ectopic expression of RB1 can suppress cyclin D1 expression in JARID2-depleted cells. Transient depletion of JARID2 in skeletal muscle cells leads to a transient up-regulation of cyclin D1 that is quickly suppressed with no resulting effect on proliferation, Taken together, we show that JARID2 and the PRC2 complex regulate skeletal muscle proliferation in a precise manner that involves the repression of cyclin D1, thus restraining proliferation and repressing RB1, which is required for mitotic exit and terminal differentiation.
-
JARID2 and the PRC2 complex regulate skeletal muscle differentiation through regulation of canonical Wnt signaling
Epigenetics & Chromatin, 2018Co-Authors: Abhinav Adhikari, Judith DavieAbstract:Background JARID2 is a non-catalytic member of the polycomb repressive complex 2 (PRC2), which is known to regulate developmental target genes in embryonic stem cells. Here, we provide mechanistic insight into the modulation of Wnt signaling by JARID2 during murine skeletal muscle differentiation. Results We show that JARID2 is expressed in proliferating myoblasts, but downregulated upon muscle differentiation. Unexpectedly, depletion of JARID2 or the catalytic subunit of the PRC2 complex, EZH2, inhibited differentiation, suggesting that JARID2 and the PRC2 complex are required to initiate this process. Expression of the myogenic regulatory factors required to promote differentiation, MYOD and MYOG, was downregulated in the absence of JARID2, even though decreases in the methylation of histone H3 lysine 27 (H3K27^me3) were observed on both promoters. We found that activation of the Wnt signaling pathway upregulated MYOD and restored differentiation. Activation of the Wnt pathway in JARID2 depleted cells caused β-catenin to translocate to the nucleus, where it bound to and activated the Myod1 promoter. We show that the Wnt antagonist SFRP1 is highly upregulated in the absence of JARID2 and is a direct target of JARID2 and the PRC2 complex. Ectopic expression of SFRP1 blocked MYOD and late muscle gene expression and inhibited the translocation of β-catenin to the nucleus. Finally, we show that JARID2 and SFRP1 are inversely correlated in melanoma, confirming that the JARID2-mediated repression of SFRP1 extends beyond skeletal muscle and has important implications in many cellular systems, including cancer. Conclusions We show that JARID2 and the PRC2 complex regulate muscle differentiation by modulating Wnt signaling through the direct repression of Wnt antagonists.
-
MOESM5 of JARID2 and the PRC2 complex regulate skeletal muscle differentiation through regulation of canonical Wnt signaling
2018Co-Authors: Abhinav Adhikari, Judith DavieAbstract:Additional file 5: Figure S5 . Expression of JARID2 and SFRP1 is better correlated in groups divided based on JARID2 expression. a, b Box plot representing the expression of JARID2 mRNA (a) and SFRP1mRNA (b) in between lower 25 percentile and upper 25th percentile, respectively (p
-
MOESM4 of JARID2 and the PRC2 complex regulate skeletal muscle differentiation through regulation of canonical Wnt signaling
2018Co-Authors: Abhinav Adhikari, Judith DavieAbstract:Additional file 4: Figure S4 . Nkd1 is not activated by JARID2 depletion. a Nkd1 mRNA is downregulated in JARID2 depleted cells as assayed by qRT-PCR. Error bars are S.E.M. **p
-
MOESM1 of JARID2 and the PRC2 complex regulate skeletal muscle differentiation through regulation of canonical Wnt signaling
2018Co-Authors: Abhinav Adhikari, Judith DavieAbstract:Additional file 1: Figure S1 . Myod1 and Myog are direct targets of the PRC2 complex. a–c Myod1 is a direct target of JARID2 and the PRC2 complex. ChIP assays using antibodies against trimethylation of lysine 27 of histone 3 (H3K27me3) and a nonspecific antibody (IgG) were performed on C2C12 cells stably expressing scr and shJARID2. Primers spanning three regulatory regions of the Myod1 promoter were used: core enhancer (CE) (a), distal regulatory region(DRR) (b) and proximal regulatory region (PRR) (c). d, e. Myogenin is a direct target of JARID2 and the PRC2 complex. Cells from (a) were differentiated for 2 days and subjected to ChIP assays performed and analyzed as in (a). Primers spanning two different regions of the myogenin promoter, 1.5-kb upstream of the transcription start site (1.5 kb) (d) and proximal promoter (Myog E1,2) (e) were used. n.s. is not statistically significant. F. H3K27me3 at the HoxB7 promoter is unaffected by depletion of JARID2. ChIP assays were performed and analyzed as in E.G. H3K9 methylation of Myod1 is not dependent on JARID2. ChIP assays using antibodies against trimethylation of lysine 9 of histone 3 (H3K9me) and a nonspecific antibody (IgG) were performed on C2C12 cells stably expressing scr and shJARID2. Primers spanning three regulatory regions of the Myod1 promoter were used: core enhancer (CE) (g), distal regulatory region (DRR) (h), and proximal regulatory region (PRR) (i). j H3K9 methylation is not observed on the Myog proximal promoter. ChIP assays were performed as in g. k H3K9 methylation is reduced on the upstream 1.5-kb region of Myog when JARID2 is depleted. ChIP assays preformed as in G. Error bars are S.E.M. **p value
Abhinav Adhikari - One of the best experts on this subject based on the ideXlab platform.
-
JARID2 and the prc2 complex regulate the cell cycle in skeletal muscle
Journal of Biological Chemistry, 2019Co-Authors: Abhinav Adhikari, Pramish Mainali, Judith DavieAbstract:JARID2 is a noncatalytic member of the polycomb repressive complex 2 (PRC2) which methylates of histone 3 lysine 27 (H3K27). In this work, we show that JARID2 and the PRC2 complex regulate the cell cycle in skeletal muscle cells to control proliferation and mitotic exit. We found that the stable depletion of JARID2 leads to increased proliferation and cell accumulation in S phase. The regulation of the cell cycle by JARID2 is mediated by direct repression of both cyclin D1 and cyclin E1, both of which are targets of PRC2-mediated H3K27 methylation. Intriguingly, we also find that the retinoblastoma protein (RB1) is a direct target of JARID2 and the PRC2 complex. The depletion of JARID2 is not sufficient to activate RB1. However, the ectopic expression of RB1 can suppress cyclin D1 expression in JARID2-depleted cells. Transient depletion of JARID2 in skeletal muscle cells leads to a transient up-regulation of cyclin D1 that is quickly suppressed with no resulting effect on proliferation, Taken together, we show that JARID2 and the PRC2 complex regulate skeletal muscle proliferation in a precise manner that involves the repression of cyclin D1, thus restraining proliferation and repressing RB1, which is required for mitotic exit and terminal differentiation.
-
JARID2 and the PRC2 complex regulate skeletal muscle differentiation through regulation of canonical Wnt signaling
Epigenetics & Chromatin, 2018Co-Authors: Abhinav Adhikari, Judith DavieAbstract:Background JARID2 is a non-catalytic member of the polycomb repressive complex 2 (PRC2), which is known to regulate developmental target genes in embryonic stem cells. Here, we provide mechanistic insight into the modulation of Wnt signaling by JARID2 during murine skeletal muscle differentiation. Results We show that JARID2 is expressed in proliferating myoblasts, but downregulated upon muscle differentiation. Unexpectedly, depletion of JARID2 or the catalytic subunit of the PRC2 complex, EZH2, inhibited differentiation, suggesting that JARID2 and the PRC2 complex are required to initiate this process. Expression of the myogenic regulatory factors required to promote differentiation, MYOD and MYOG, was downregulated in the absence of JARID2, even though decreases in the methylation of histone H3 lysine 27 (H3K27^me3) were observed on both promoters. We found that activation of the Wnt signaling pathway upregulated MYOD and restored differentiation. Activation of the Wnt pathway in JARID2 depleted cells caused β-catenin to translocate to the nucleus, where it bound to and activated the Myod1 promoter. We show that the Wnt antagonist SFRP1 is highly upregulated in the absence of JARID2 and is a direct target of JARID2 and the PRC2 complex. Ectopic expression of SFRP1 blocked MYOD and late muscle gene expression and inhibited the translocation of β-catenin to the nucleus. Finally, we show that JARID2 and SFRP1 are inversely correlated in melanoma, confirming that the JARID2-mediated repression of SFRP1 extends beyond skeletal muscle and has important implications in many cellular systems, including cancer. Conclusions We show that JARID2 and the PRC2 complex regulate muscle differentiation by modulating Wnt signaling through the direct repression of Wnt antagonists.
-
JARID2 and the PRC2 complex regulate skeletal muscle differentiation through regulation of canonical Wnt signaling
Epigenetics & chromatin, 2018Co-Authors: Abhinav Adhikari, Judith K. DavieAbstract:JARID2 is a non-catalytic member of the polycomb repressive complex 2 (PRC2), which is known to regulate developmental target genes in embryonic stem cells. Here, we provide mechanistic insight into the modulation of Wnt signaling by JARID2 during murine skeletal muscle differentiation. We show that JARID2 is expressed in proliferating myoblasts, but downregulated upon muscle differentiation. Unexpectedly, depletion of JARID2 or the catalytic subunit of the PRC2 complex, EZH2, inhibited differentiation, suggesting that JARID2 and the PRC2 complex are required to initiate this process. Expression of the myogenic regulatory factors required to promote differentiation, MYOD and MYOG, was downregulated in the absence of JARID2, even though decreases in the methylation of histone H3 lysine 27 (H3K27me3) were observed on both promoters. We found that activation of the Wnt signaling pathway upregulated MYOD and restored differentiation. Activation of the Wnt pathway in JARID2 depleted cells caused β-catenin to translocate to the nucleus, where it bound to and activated the Myod1 promoter. We show that the Wnt antagonist SFRP1 is highly upregulated in the absence of JARID2 and is a direct target of JARID2 and the PRC2 complex. Ectopic expression of SFRP1 blocked MYOD and late muscle gene expression and inhibited the translocation of β-catenin to the nucleus. Finally, we show that JARID2 and SFRP1 are inversely correlated in melanoma, confirming that the JARID2-mediated repression of SFRP1 extends beyond skeletal muscle and has important implications in many cellular systems, including cancer. We show that JARID2 and the PRC2 complex regulate muscle differentiation by modulating Wnt signaling through the direct repression of Wnt antagonists.
-
MOESM5 of JARID2 and the PRC2 complex regulate skeletal muscle differentiation through regulation of canonical Wnt signaling
2018Co-Authors: Abhinav Adhikari, Judith DavieAbstract:Additional file 5: Figure S5 . Expression of JARID2 and SFRP1 is better correlated in groups divided based on JARID2 expression. a, b Box plot representing the expression of JARID2 mRNA (a) and SFRP1mRNA (b) in between lower 25 percentile and upper 25th percentile, respectively (p
-
MOESM4 of JARID2 and the PRC2 complex regulate skeletal muscle differentiation through regulation of canonical Wnt signaling
2018Co-Authors: Abhinav Adhikari, Judith DavieAbstract:Additional file 4: Figure S4 . Nkd1 is not activated by JARID2 depletion. a Nkd1 mRNA is downregulated in JARID2 depleted cells as assayed by qRT-PCR. Error bars are S.E.M. **p
Siming Chen - One of the best experts on this subject based on the ideXlab platform.
-
Unique Structural Platforms of Suz12 Dictate Distinct Classes of PRC2 for Chromatin Binding.
Molecular Cell, 2018Co-Authors: Siming Chen, Lianying Jiao, Murtada Shubbar, Xin YangAbstract:Summary Developmentally regulated accessory subunits dictate PRC2 function. Here, we report the crystal structures of a 120 kDa heterotetrameric complex consisting of Suz12, Rbbp4, JARID2, and Aebp2 fragments that is minimally active in nucleosome binding and of an inactive binary complex of Suz12 and Rbbp4. Suz12 contains two unique structural platforms that define distinct classes of PRC2 holo complexes for chromatin binding. Aebp2 and Phf19 compete for binding of a non-canonical C2 domain of Suz12; JARID2 and EPOP occupy an overlapped Suz12 surface required for chromatin association of PRC2. Suz12 and Aebp2 progressively block histone H3K4 binding to Rbbp4, suggesting that Rbbp4 may not be directly involved in PRC2 inhibition by the active H3K4me3 histone mark. Nucleosome binding enabled by JARID2 and Aebp2 is in part accounted for by the structures, which also reveal that disruption of the JARID2-Suz12 interaction may underlie the disease mechanism of an oncogenic chromosomal translocation of Suz12.
-
Unique Structural Platforms of Suz12 Dictate Distinct Classes of PRC2 for Chromatin Binding.
Molecular Cell, 2018Co-Authors: Siming Chen, Lianying Jiao, Murtada Shubbar, Xin YangAbstract:Summary Developmentally regulated accessory subunits dictate PRC2 function. Here, we report the crystal structures of a 120 kDa heterotetrameric complex consisting of Suz12, Rbbp4, JARID2, and Aebp2 fragments that is minimally active in nucleosome binding and of an inactive binary complex of Suz12 and Rbbp4. Suz12 contains two unique structural platforms that define distinct classes of PRC2 holo complexes for chromatin binding. Aebp2 and Phf19 compete for binding of a non-canonical C2 domain of Suz12; JARID2 and EPOP occupy an overlapped Suz12 surface required for chromatin association of PRC2. Suz12 and Aebp2 progressively block histone H3K4 binding to Rbbp4, suggesting that Rbbp4 may not be directly involved in PRC2 inhibition by the active H3K4me3 histone mark. Nucleosome binding enabled by JARID2 and Aebp2 is in part accounted for by the structures, which also reveal that disruption of the JARID2-Suz12 interaction may underlie the disease mechanism of an oncogenic chromosomal translocation of Suz12.