Polycomb group protein CBX7 represses cardiomyocyte proliferation via modulation of the TARDBP/Rbm38 axis

SummaryCardiomyocyte (CM) proliferation notably decreases during the perinatal period. At present, regulatory mechanisms for this loss of proliferative capacity is poorly understood. CBX7, a polycomb group (PcG) protein, regulates the cell cycle but its role in CM proliferation is unknown. Here, we report that CBX7 inhibits proliferation of perinatal CMs by controlling TARDBP/Rbm38 pathway. Gene expression profiling demonstrated that CBX7 expression in the heart was low during the prenatal period, abruptly increased during the perinatal period, and sustained constantly throughout the adulthood. CBX7, when overexpressed via adenoviral transduction in neonatal CMs, reduced proliferation and promoted multinucleation of the CMs. Mutant mice carrying targeted inhibition of CBX7 in CMs exhibited cardiomegaly with increased proliferation of CMs at postnatal stages. Mechanistically, CBX7 interacted with TAR DNA-binding protein 43 (TARDBP) and positively regulated its downstream target, RNA Binding Motif Protein 38 (RBM38). Rbm38 was upregulated in the postnatal hearts and overexpression of RBM38 reduced proliferation of neonatal CMs. Together, this study provides a novel insight into the role of CBX7 in regulation of CM proliferation during the perinatal period.

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Interactions with RNA direct the Polycomb group protein SCML2 to chromatin where it represses target genes

eLife ◽

10.7554/elife.02637 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 32

Author(s):

Roberto Bonasio ◽

Emilio Lecona ◽

Varun Narendra ◽

Philipp Voigt ◽

Fabio Parisi ◽

...

Keyword(s):

Gene Expression ◽

Epigenetic Regulation ◽

Target Genes ◽

Rna Binding ◽

Regulation Of Gene Expression ◽

Polycomb Group ◽

Polycomb Group Protein ◽

Binding Region ◽

Group Protein ◽

Polycomb Repressive Complex 1

Polycomb repressive complex-1 (PRC1) is essential for the epigenetic regulation of gene expression. SCML2 is a mammalian homolog of Drosophila SCM, a Polycomb-group protein that associates with PRC1. In this study, we show that SCML2A, an SCML2 isoform tightly associated to chromatin, contributes to PRC1 localization and also directly enforces repression of certain Polycomb target genes. SCML2A binds to PRC1 via its SPM domain and interacts with ncRNAs through a novel RNA-binding region (RBR). Targeting of SCML2A to chromatin involves the coordinated action of the MBT domains, RNA binding, and interaction with PRC1 through the SPM domain. Deletion of the RBR reduces the occupancy of SCML2A at target genes and overexpression of a mutant SCML2A lacking the RBR causes defects in PRC1 recruitment. These observations point to a role for ncRNAs in regulating SCML2 function and suggest that SCML2 participates in the epigenetic control of transcription directly and in cooperation with PRC1.

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Dominant-negative C/ebpα and polycomb group protein Bmi1 extend short-lived hematopoietic stem/progenitor cell life span and induce lethal dyserythropoiesis

Blood ◽

10.1182/blood-2010-12-327908 ◽

2011 ◽

Vol 118 (14) ◽

pp. 3842-3852 ◽

Cited By ~ 9

Author(s):

Ting Zhou ◽

Lei Wang ◽

Kang-Yong Zhu ◽

Mei Dong ◽

Peng-Fei Xu ◽

...

Keyword(s):

Life Span ◽

Dominant Negative ◽

Polycomb Group ◽

Binding Motif ◽

Polycomb Group Protein ◽

Self Renewal ◽

Hematopoietic Stem ◽

Group Protein ◽

Targeted Expression ◽

Transgenic Embryos

Abstract The primitive hematopoietic stem/progenitor cells (HSPCs) during embryonic hematopoiesis are thought to be short-lived (SL) with limited self-renewal potential. The fate and consequence of these short-lived HSPCs, once reprogrammed into “long-lived” in a living animal body, remain unknown. Here we show that targeted expression of a dominant-negative C/ebpα (C/ebpαDN) in the primitive SL-HSPCs during zebrafish embryogenesis extends their life span, allowing them to survive to later developmental stage to colonize the definitive hematopoietic sites, where they undergo a proliferative expansion followed by erythropoietic dysplasia and embryonic lethality because of circulation congestion. Mechanistically, C/ebpαDN binds to a conserved C/EBP-binding motif in the promoter region of bmi1 gene, associated with a specific induction of bmi1 transcription in the transgenic embryos expressing C/ebpαDN. Targeted expression of Bmi1 in the SL-HSPCs recapitulates nearly all aberrant phenotypes induced by C/ebpαDN, whereas knockdown of bmi1 largely rescues these abnormalities. The results indicate that Bmi1 acts immediately downstream of C/ebpαDN to regulate the survival and self-renewal of HSPCs and contribute to the erythropoietic dysplasia.

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