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

Human globin gene production transcriptionally “switches” from fetal to adult synthesis shortly after birth and is controlled by macromolecular complexes that enhance or suppress transcription by cis elements scattered throughout the locus. The DRED (direct repeat erythroid-definitive) repressor is...

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Autores principales: Yu, Lei, Jearawiriyapaisarn, Natee, Lee, Mary P., Hosoya, Tomonori, Wu, Qingqing, Myers, Greggory, Lim, Kim-Chew, Kurita, Ryo, Nakamura, Yukio, Vojtek, Anne B., Rual, Jean-François, Engel, James Douglas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295165/
https://www.ncbi.nlm.nih.gov/pubmed/30463901
http://dx.doi.org/10.1101/gad.318436.118
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author Yu, Lei
Jearawiriyapaisarn, Natee
Lee, Mary P.
Hosoya, Tomonori
Wu, Qingqing
Myers, Greggory
Lim, Kim-Chew
Kurita, Ryo
Nakamura, Yukio
Vojtek, Anne B.
Rual, Jean-François
Engel, James Douglas
author_facet Yu, Lei
Jearawiriyapaisarn, Natee
Lee, Mary P.
Hosoya, Tomonori
Wu, Qingqing
Myers, Greggory
Lim, Kim-Chew
Kurita, Ryo
Nakamura, Yukio
Vojtek, Anne B.
Rual, Jean-François
Engel, James Douglas
author_sort Yu, Lei
collection PubMed
description Human globin gene production transcriptionally “switches” from fetal to adult synthesis shortly after birth and is controlled by macromolecular complexes that enhance or suppress transcription by cis elements scattered throughout the locus. The DRED (direct repeat erythroid-definitive) repressor is recruited to the ε-globin and γ-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA-binding and epigenetic enzyme components (e.g., DNA methyltransferase 1 [DNMT1] and lysine-specific demethylase 1 [LSD1]) that elicit DRED function. We also describe a potent new regulator of γ-globin repression: The deubiquitinase BRCA1-associated protein-1 (BAP1) is a component of the repressor complex whose activity maintains NCoR1 at sites in the β-globin locus, and BAP1 inhibition in erythroid cells massively induces γ-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate γ-globin gene repression.
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spelling pubmed-62951652019-06-01 BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression Yu, Lei Jearawiriyapaisarn, Natee Lee, Mary P. Hosoya, Tomonori Wu, Qingqing Myers, Greggory Lim, Kim-Chew Kurita, Ryo Nakamura, Yukio Vojtek, Anne B. Rual, Jean-François Engel, James Douglas Genes Dev Research Paper Human globin gene production transcriptionally “switches” from fetal to adult synthesis shortly after birth and is controlled by macromolecular complexes that enhance or suppress transcription by cis elements scattered throughout the locus. The DRED (direct repeat erythroid-definitive) repressor is recruited to the ε-globin and γ-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA-binding and epigenetic enzyme components (e.g., DNA methyltransferase 1 [DNMT1] and lysine-specific demethylase 1 [LSD1]) that elicit DRED function. We also describe a potent new regulator of γ-globin repression: The deubiquitinase BRCA1-associated protein-1 (BAP1) is a component of the repressor complex whose activity maintains NCoR1 at sites in the β-globin locus, and BAP1 inhibition in erythroid cells massively induces γ-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate γ-globin gene repression. Cold Spring Harbor Laboratory Press 2018-12-01 /pmc/articles/PMC6295165/ /pubmed/30463901 http://dx.doi.org/10.1101/gad.318436.118 Text en © 2018 Yu et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Yu, Lei
Jearawiriyapaisarn, Natee
Lee, Mary P.
Hosoya, Tomonori
Wu, Qingqing
Myers, Greggory
Lim, Kim-Chew
Kurita, Ryo
Nakamura, Yukio
Vojtek, Anne B.
Rual, Jean-François
Engel, James Douglas
BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression
title BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression
title_full BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression
title_fullStr BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression
title_full_unstemmed BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression
title_short BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression
title_sort bap1 regulation of the key adaptor protein ncor1 is critical for γ-globin gene repression
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295165/
https://www.ncbi.nlm.nih.gov/pubmed/30463901
http://dx.doi.org/10.1101/gad.318436.118
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