BAP1 deubiquitinase is a potent repressor of fetal hemoglobin biosynthesis [article]

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
2018 bioRxiv   pre-print
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
more » ... 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.
doi:10.1101/346619 fatcat:25zxe3oabzdchm7zl2pi4zzzeq