Histone H2A monoubiquitination and Polycomb repression

Scheuermann, Johanna C.; Gutiérrez, L.; Müller, Jürg

doi:10.4161/fly.20986

Cited by 43 publications

(35 citation statements)

References 49 publications

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“…However, whether H2A-ubiquitination per se functions as a repression marker is still an open question in the field (18,19). Indeed, other studies showed that the repression of certain target genes requires not only the PRC1-mediated H2A ubiquitination, but also PR-DUB-mediated H2A DUB, which suggests that, at least in some contexts, an appropriate balance between H2A ubiquitination and DUB, rather than H2A ubiquitination per se, is important for the maintenance of target gene repression (20). Our data showed that glucose starvation promotes the binding of not only BAP1, but also BMI1 and RING1B, two integral and critical components of PRC1, on ATF3/CHOP promoters, and that inactivation of either BAP1 or BMI1 similarly enhances ATF3 or CHOP expression in response to glucose deprivation.…”

Section: Discussionmentioning

confidence: 99%

BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response

Dai

Lee

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The endoplasmic reticulum (ER) is classically linked to metabolic homeostasis via the activation of unfolded protein response (UPR), which is instructed by multiple transcriptional regulatory cascades. BRCA1 associated protein 1 (BAP1) is a tumor suppressor with deubiquitinating enzyme activity and has been implicated in chromatin regulation of gene expression. Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress. This prosurvival role of BAP1 depends on its de-ubiquitinating activity and correlates with its ability to dampen the metabolic stress-induced UPR transcriptional network. BAP1 inhibits glucose deprivation-induced reactive oxygen species and ATP depletion, two cellular events contributing to the ER stress-induced cell death. In line with this, Bap1 KO mice are more sensitive to tunicamycin-induced renal damage. Mechanically, we show that BAP1 represses metabolic stress-induced UPR and cell death through activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP), and reveal that BAP1 binds to ATF3 and CHOP promoters and inhibits their transcription. Taken together, our results establish a previously unappreciated role of BAP1 in modulating the cellular adaptability to metabolic stress and uncover a pivotal function of BAP1 in the regulation of the ER stress gene-regulatory network. Our study may also provide new conceptual framework for further understanding BAP1 function in cancer.BAP1 | ER stress | unfolded protein response | energy stress | glucose starvation A nimal cells rely on nutrient supplies (e.g., glucose, and oxygen) to generate energy and biomaterials and to maintain cellular homeostasis under both physiological and pathological conditions. The metabolic stress response, defined as how cells respond to the lack of nutrient supplies in an adaptive or suicidal manner, is therefore essential to cellular functions and survival. Cells use multiple signaling cascades to adapt cellular functions and control cell fate in a manner dependent on the duration and strength of stress (1). Elucidating the molecular mechanisms of metabolic stress response is thus important for more in-depth understanding of organism development and human disease.The evolutionarily conserved unfolded protein response (UPR) protects cells against the stress of misfolded proteins in the endoplasmic reticulum (ER) for continued survival, and will initiate regulated cell death if the ER stress cannot be resolved (2). The key to UPR-mediated cell fate decision is the gene-expression network driven by the ER stress-activated transcriptional factors (TFs) (3). The canonical UPR TFs include X-box binding protein 1 (XBP1), activating transcription factor 6 (ATF6), ATF4, and C/EBP homologous protein (CHOP), which function downstream of three ER-localized stress sensors: inositol-requiring enzyme 1α (IRE1α), ATF6, and double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK), respectively. Of the UPR gene regulatory network, the ATF4/CHOP arm mediates expression of genes th...

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Section: Discussionmentioning

confidence: 99%

BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response

Dai

Lee

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the PR-DUB complex is not generally associated with transcriptional activation mechanisms and instead appears to be repressive in nature, potentially through promoting histone ubiquitination dynamics (reviewed in (39)). Indeed, this is consistent with our demonstration that BAP1 depletion causes increased ubiquitination levels at regulatory regions associated with genes that are either repressed or activated under the same conditions (see Figures 5C and 6C).…”

Section: Discussionmentioning

confidence: 99%

The forkhead transcription factor FOXK2 acts as a chromatin targeting factor for the BAP1-containing histone deubiquitinase complex

Mohammed

Webber

et al. 2014

Nucleic Acids Research

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There are numerous forkhead transcription factors in mammalian cells but we know little about the molecular functions of the majority of these. FOXK2 is a ubiquitously expressed family member suggesting an important function across multiple cell types. Here, we show that FOXK2 binds to the SIN3A and PR-DUB complexes. The PR-DUB complex contains the important tumour suppressor protein, the deubiquitinase BAP1. FOXK2 recruits BAP1 to DNA, promotes local histone deubiquitination and causes changes in target gene activity. Our results therefore provide an important link between BAP1 and the transcription factor FOXK2 and demonstrate how BAP1 can be recruited to specific regulatory loci.

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“…We speculate that there may also be other transcription factors to mediate BAP1 recruitment to target gene promoters. Because histone H2A ubiquitination mediates epigenetic silencing (Scheuermann et al, 2012), downregulation of S phase genes following BAP1 depletion may be the result of increased H2AK119ub1 binding to the promoters. Taken together, the results indicate that HCF-1 may serve as a scaffold protein that recruits the chromatin modifying protein BAP1 to the E2F responsive promoters to precisely control gene expression through the modification of histone H2A.…”

Section: Bap1 Is Crucial For Histone H2a Deubiquitinationmentioning

confidence: 99%

BAP1 regulates cell cycle progression through E2F1 target genes and mediates transcriptional silencing via H2A monoubiquitination in uveal melanoma cells

Pan

Jia

Zhang

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Histone H2A monoubiquitination and Polycomb repression

Cited by 43 publications

References 49 publications

BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response

BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response

The forkhead transcription factor FOXK2 acts as a chromatin targeting factor for the BAP1-containing histone deubiquitinase complex

BAP1 regulates cell cycle progression through E2F1 target genes and mediates transcriptional silencing via H2A monoubiquitination in uveal melanoma cells

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