BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression

Yu, Li; Jearawiriyapaisarn, Natee; Lee, Mary P.; Hosoya, Takamitsu; Wu, Qingqing; Myers, Greggory; Lim, Kim-Chew; Kurita, Ryo; Nakamura, Yukio; Vojtek, Anne B.; Rual, Jean François; Engel, James Douglas

doi:10.1101/gad.318436.118

Cited by 28 publications

(25 citation statements)

References 52 publications

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“…It should be noted that we cannot formally exclude involvement of corepressors other than NCOR and SMRT in PT-S264-dependent repression. Genetic deletion of NCOR1 was unsuccessful in our hands; this is consistent with the notions that NCOR function may be necessary for regulation of the cell cycle (91), genome stability (92), or other critical processes (62). Cellular models without this limitation or knock-in approaches might be suitable to resolve whether NCOR and SMRT complexes are sufficient for repression by PPARβ/δ inverse agonists.…”

Section: Discussionsupporting

confidence: 87%

PPARβ/δ recruits NCOR and regulates transcription reinitiation of ANGPTL4

Legrand

Bretscher

Zielke

et al. 2019

Nucleic Acids Research

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In the absence of ligands, the nuclear receptor PPARβ/δ recruits the NCOR and SMRT corepressors, which form complexes with HDAC3, to canonical target genes. Agonistic ligands cause dissociation of corepressors and enable enhanced transcription. Vice versa, synthetic inverse agonists augment corepressor recruitment and repression. Both basal repression of the target gene ANGPTL4 and reinforced repression elicited by inverse agonists are partially insensitive to HDAC inhibition. This raises the question how PPARβ/δ represses transcription mechanistically. We show that the PPARβ/δ inverse agonist PT-S264 impairs transcription initiation by decreasing recruitment of activating Mediator subunits, RNA polymerase II, and TFIIB, but not of TFIIA, to the ANGPTL4 promoter. Mass spectrometry identifies NCOR as the main PT-S264-dependent interactor of PPARβ/δ. Reconstitution of knockout cells with PPARβ/δ mutants deficient in basal repression results in diminished recruitment of NCOR, SMRT, and HDAC3 to PPAR target genes, while occupancy by RNA polymerase II is increased. PT-S264 restores binding of NCOR, SMRT, and HDAC3 to the mutants, resulting in reduced polymerase II occupancy. Our findings corroborate deacetylase-dependent and -independent repressive functions of HDAC3-containing complexes, which act in parallel to downregulate transcription.

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Section: Discussionsupporting

confidence: 87%

PPARβ/δ recruits NCOR and regulates transcription reinitiation of ANGPTL4

Legrand

Bretscher

Zielke

et al. 2019

Nucleic Acids Research

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“…BAP1 was shown to deubiquitinate HCF-1 at the N-terminus, which is essential for BAP1 binding and BAP1-dependent cell growth inhibition 10 . Other epigenetic/transcription factors such as Krueppel-like factor 5 (KLF5) 37 , chromatin-remodeling ATPase INO80 38 , DNA methyltransferase 1 (DNMT1) 39 , nuclear receptor corepressor-1 (NCoR1) 40 , peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) 41 , and type 3 inositol-1,4,5-trisphosphate receptor (IP3R3) 42 are all identified as BAP1 unique non-histone substrates (Fig. 2D ).…”

Section: The Functions Of the Bap1 Complex At The Chromatin Levelmentioning

confidence: 99%

Emerging multifaceted roles of BAP1 complexes in biological processes

Szczepanski

Wang

2021

Cell Death Discov.

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Histone H2AK119 mono-ubiquitination (H2AK119Ub) is a relatively abundant histone modification, mainly catalyzed by the Polycomb Repressive Complex 1 (PRC1) to regulate Polycomb-mediated transcriptional repression of downstream target genes. Consequently, H2AK119Ub can also be dynamically reversed by the BAP1 complex, an evolutionarily conserved multiprotein complex that functions as a general transcriptional activator. In previous studies, it has been reported that the BAP1 complex consists of important biological roles in development, metabolism, and cancer. However, identifying the BAP1 complex’s regulatory mechanisms remains to be elucidated due to its various complex forms and its ability to target non-histone substrates. In this review, we will summarize recent findings that have contributed to the diverse functional role of the BAP1 complex and further discuss the potential in targeting BAP1 for therapeutic use.

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“…ChIP. ChIP assays were conducted as described previously 26 . Table 1) and verified by Sanger sequencing.…”

Section: Hplcmentioning

confidence: 99%

“…We previously reported that TR2/TR4 directly binds to the g-globin promoter to recruit a multimeric Direct Repeat Erythroid-Definitive (DRED) multi-subunit protein complex to repress g-globin transcription in adult erythroid cells 21,22 . The core co-repressor subunits of both the DRED complex and BCL11a include a scaffold protein, NCoR1, which recruits the epigenetic chromatin modifying enzymes DNMT1 and LSD1, among several others [25][26][27] . LSD1/KDM1A is a flavin adenine dinucleotide-dependent histone demethylase that is specific for methylated histone H3 lysine 4 and 9 (H3K4 and H3K9) 28,29 .…”

Section: Introductionmentioning

confidence: 99%

The epigenetic eraser LSD1 lies at the apex of a reversible erythroid to myeloid cell fate decision

Myers

et al. 2021

Preprint

Self Cite

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Histone H3 lysine 4 methylation (H3K4Me) is proximally associated with chromatin activation, and therefore removing H3K4 methyl groups is normally coincident with gene repression. H3K4Me demethylase KDM1a/LSD1 is a potential therapeutic target for multiple diseases, including for the treatment of the β-globinopathies (sickle cell disease and β-thalassemia) since it is a component of multiple γ-globin repressor complexes, and its inactivation leads to robust induction of the fetal globin genes. However, the effects of LSD1 inhibition in definitive erythroid cells are not well characterized. Here we examined the consequences of erythroid-specific conditional inactivation of Lsd1 in vivo using a new Gata1creERT2 bacterial artificial chromosome (BAC) transgene. Conditional loss of Lsd1 in adult mice led to a differentiation block in erythroid progenitor cells and the surprising expansion of a GMP-like cell pool, apparently converting hematopoietic differentiation potential from an erythroid to a myeloid fate. The analogous phenotype was also observed in human cells: inactivation of LSD1 in hematopoietic stem and progenitor cells (HSPC) also blocked erythroid differentiation, coincident with robust induction of myeloid transcription factor genes (e.g. Pu.1 and Cebpa). Remarkably, blocking the activity of PU.1 or RUNX1 (a transcriptional activator of Pu.1) at the same time as blocking LSD1 activity reverted the myeloid lineage conversion back to an erythroid phenotype. Taken together, the data show that LSD1 maintains erythropoiesis by reversibly repressing a myeloid cell fate in adult erythroid cell precursors, and that inhibition of the myeloid differentiation pathway can reverse the negative effects of LSD1 inactivation on erythroid differentiation.

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BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression

Cited by 28 publications

References 52 publications

PPARβ/δ recruits NCOR and regulates transcription reinitiation of ANGPTL4

PPARβ/δ recruits NCOR and regulates transcription reinitiation of ANGPTL4

Emerging multifaceted roles of BAP1 complexes in biological processes

The epigenetic eraser LSD1 lies at the apex of a reversible erythroid to myeloid cell fate decision

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