The Polycomb Repressive Complex 1 Protein BMI1 Is Required for Constitutive Heterochromatin Formation and Silencing in Mammalian Somatic Cells

Abdouh, Mohamed; Hanna, Roy; Hajjar, Jida El; Flamier, Anthony; Bernier, Gilbert

doi:10.1074/jbc.m115.662403

Cited by 34 publications

(37 citation statements)

References 79 publications

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“…This is consistent with previously published findings that H2AK119 monoubiquitination by PRC1 is associated with gene repression (Cao et al, 2005; Wang et al, 2004). It is also possible that knockdown of Bmi1 de-compacted chromatin and increased DNA accessibility (Abdouh et al, 2016; Eskeland et al, 2010; Francis et al, 2004; Levine et al, 2002; Shao et al, 1999), thereby de-repressing Gata4 and the other cardiogenic genes. Interestingly, this de-repression of endogenous Gata4 by Bmi1 depletion could substitute for exogenous Gata4 in reprogramming fibroblasts into beating iCMs, demonstrating that removing certain epigenetic barrier(s) could allow for efficient iCM generation with fewer transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming

et al. 2016

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SUMMARY Direct reprogramming of induced cardiomyocytes (iCMs) suffers from low efficiency and requires extensive epigenetic repatterning, although the underlying mechanisms are largely unknown. To address these issues, we screened for epigenetic regulators of iCM reprogramming and found that reducing levels of the polycomb complex gene Bmi1 significantly enhanced induction of beating iCMs from neonatal and adult mouse fibroblasts. The inhibitory role of Bmi1 in iCM reprogramming is mediated through direct interactions with regulatory regions of cardiogenic genes, rather than regulation of cell proliferation. Reduced Bmi1 expression corresponded with increased levels of the active histone mark H3K4me3 and reduced levels of repressive H2AK199ub at cardiogenic loci, and de-repression of cardiogenic gene expression during iCM conversion. Furthermore, Bmi1 deletion could substitute for Gata4 during iCM reprogramming. Thus, Bmi1 acts as a critical epigenetic barrier to iCM production. Bypassing this barrier simplifies iCM generation and increases yield, potentially streamlining iCM production for therapeutic purposes.

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Section: Discussionmentioning

confidence: 99%

Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming

et al. 2016

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“…The polycomb-group (PcG) proteins traditionally represent another type of chromatin repression normally enriched on facultative heterochromatin together with H3K27me3 and H2AK119ub, and are traditionally not considered associating with pericentromeric heterochromatin (18,19). However, several studies have demonstrated that under some circumstances, PcG proteins can be found on pericentromeric satellite DNA (20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Reprogramming of Pericentromeric Satellite DNA in Premalignant and Malignant Lesions

Brückmann

Pedersen

Ditzel

et al. 2018

Molecular Cancer Research

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Repression of repetitive DNA is important for maintaining genomic stability, but is often perturbed in cancer. For instance, the megabase satellite domain at chromosome 1q12 is a common site of genetic rearrangements, such as translocations and deletions. Polycomb-group proteins can be observed as large subnuclear domains called polycomb bodies, the composition and cellular function of which has remained elusive. This study demonstrates that polycomb bodies are canonical subunits of the multiprotein polycomb repressive complex 1 deposited on 1q12 pericentromeric satellite DNA, which are normally maintained as constitutive heterochromatin by other mechanisms. Furthermore, the data reveal that polycomb bodies are exclusive to premalignant and malignant cells, being absent in normal cells. For instance, polycomb bodies are present in melanocytic cells of nevi and conserved in primary and metastatic melanomas. Deposition of polycomb on the 1q12 satellite DNA in melanoma development correlated with reduced DNA methylation levels. In agreement with this, inhibition of DNA methyltransferases, with the hypomethylating agent guadecitabine (SGI-110), was sufficient for polycomb body formation on pericentromeric satellites in primary melanocytes. This suggests that polycomb bodies form in cancer cells with global DNA demethylation to control the stability of pericentromeric satellite DNA. These results reveal a novel epigenetic perturbation specific to premalignant and malignant cells that may be used as an early diagnostic marker for detection of precancerous changes and a new therapeutic entry point. Pericentromeric satellite DNA is epigenetically reprogrammed into polycomb bodies as a premalignant event with implications for transcriptional activity and genomic stability. .

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“…Although PcG proteins are generally considered regulators of facultative chromatin, thus regulating gene expression, PcG proteins have also been demonstrated to be involved in the formation of constitutive heterochromatin [16,[42][43][44][45]. Constitutive heterochromatin is found mainly at the centromeric and telomeric regions of chromosomes, which are gene-poor regions crucial for maintaining structural organization of chromosomes and genomic integrity.…”

Section: The Role Of Pcg Complexes In Repression Of Pericentromeric Hmentioning

confidence: 99%

“…PCH is kept in an inactive state by the continuous repression facilitated by the SUV39H/H3K9me3/HP1/DNMT pathway. However, in specific developmental settings [16,[42][43][44] or in malignancies [45,[50][51][52], hypomethylation of PCH allows the deposition of PcG. In early mouse preimplantation embryos, maternal PCH is enriched in H3K9me3, HP1 and H4K20me3 mediated by SUV39H1/2 and SUV420H1/2.…”

Section: The Role Of Pcg Complexes In Repression Of Pericentromeric Hmentioning

confidence: 99%

“…Several studies have investigated the relationship between H3K9me3, CGI methylation and PcG recruitment to PCH in human and mice embryonic stem cells [16,[42][43][44]54], and found that PRC2 recruitment correlates with loss of methylation. In this regard, it has been suggested that H3K9me3/HP1 and methylated CGI antagonize PRC recruitment, and thus inhibition of SUV39H/DNMT and complete loss of H3K9me3/HP1 and CGI methylation allows PRC recruitment and activity.…”

Section: The Role Of Pcg Complexes In Repression Of Pericentromeric Hmentioning

confidence: 99%

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Interaction between Polycomb and SSX Proteins in Pericentromeric Heterochromatin Function and Its Implication in Cancer

Johansen

Gjerstorff

2020

Cells

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The stability of pericentromeric heterochromatin is maintained by repressive epigenetic control mechanisms, and failure to maintain this stability may cause severe diseases such as immune deficiency and cancer. Thus, deeper insight into the epigenetic regulation and deregulation of pericentromeric heterochromatin is of high priority. We and others have recently demonstrated that pericentromeric heterochromatin domains are often epigenetically reprogrammed by Polycomb proteins in premalignant and malignant cells to form large subnuclear structures known as Polycomb bodies. This may affect the regulation and stability of pericentromeric heterochromatin domains and/or the distribution of Polycomb factors to support tumorigeneses. Importantly, Polycomb bodies in cancer cells may be targeted by the cancer/testis-related SSX proteins to cause derepression and genomic instability of pericentromeric heterochromatin. This review will discuss the interplay between SSX and Polycomb factors in the repression and stability of pericentromeric heterochromatin and its possible implications for tumor biology.

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The Polycomb Repressive Complex 1 Protein BMI1 Is Required for Constitutive Heterochromatin Formation and Silencing in Mammalian Somatic Cells

Cited by 34 publications

References 79 publications

Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming

Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming

Epigenetic Reprogramming of Pericentromeric Satellite DNA in Premalignant and Malignant Lesions

Interaction between Polycomb and SSX Proteins in Pericentromeric Heterochromatin Function and Its Implication in Cancer

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