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BAP1 deubiquitinase is a potent repressor of fetal hemoglobin biosynthesis
release_25zxe3oabzdchm7zl2pi4zzzeq
by
Lei Yu,
Natee Jearawiriyapaisarn,
Mary P Lee,
Tomonori Hosoya,
Qingqing Wu,
Greggory Myers,
Kim Chew Lim,
Ryo Kurita,
Yukio Nakamura,
Anne B Vojtek,
Jean-Francois Rual,
James Engel
Released
as a post
by Cold Spring Harbor Laboratory.
2018
Abstract
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 repressor is recruited to the epsilon- and gamma-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. DNMT1 and LSD1) that elicit DRED function. We also describe a potent new regulator of gamma-globin repression: the deubiquitinase BAP1 is a component of the repressor complex whose activity maintains NCoR1 at sites in the beta-globin locus, and BAP1 inhibition in erythroid cells massively induces gamma-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate gamma-globin gene repression.
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Date 2018-06-13
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Date 2018-06-13
DOI
10.1101/346619
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