Functions of BET proteins in erythroid gene expression.

Abstract:

:Inhibitors of bromodomain and extraterminal motif proteins (BETs) are being evaluated for the treatment of cancer and other diseases, yet much remains to be learned about how BET proteins function during normal physiology. We used genomic and genetic approaches to examine BET function in a hematopoietic maturation system driven by GATA1, an acetylated transcription factor previously shown to interact with BETs. We found that BRD2, BRD3, and BRD4 were variably recruited to GATA1-regulated genes, with BRD3 binding the greatest number of GATA1-occupied sites. Pharmacologic BET inhibition impaired GATA1-mediated transcriptional activation, but not repression, genome-wide. Mechanistically, BETs promoted chromatin occupancy of GATA1 and subsequently supported transcriptional activation. Using a combination of CRISPR-Cas9-mediated genomic engineering and shRNA approaches, we observed that depletion of either BRD2 or BRD4 alone blunted erythroid gene activation. Surprisingly, depletion of BRD3 only affected erythroid transcription in the context of BRD2 deficiency. Consistent with functional overlap among BET proteins, forced BRD3 expression substantially rescued defects caused by BRD2 deficiency. These results suggest that pharmacologic BET inhibition should be interpreted in the context of distinct steps in transcriptional activation and overlapping functions among BET family members.

journal_name

Blood

journal_title

Blood

authors

Stonestrom AJ,Hsu SC,Jahn KS,Huang P,Keller CA,Giardine BM,Kadauke S,Campbell AE,Evans P,Hardison RC,Blobel GA

doi

10.1182/blood-2014-10-607309

subject

Has Abstract

pub_date

2015-04-30 00:00:00

pages

2825-34

issue

18

eissn

0006-4971

issn

1528-0020

pii

blood-2014-10-607309

journal_volume

125

pub_type

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