Open AccessFunctional coordination of BET family proteins underlies altered transcription associated with memory impairment in fragile X syndrome
Author(s) -
Seung Kyoon Kim,
Xihui Liu,
Jong-Min Park,
Dahun Um,
Gokhul Kilaru,
Cheng Ming Chiang,
Min-Hee Kang,
Kimberly M. Huber,
Keunsoo Kang,
Tae Kyung Kim
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abf7346
Subject(s) - bromodomain , brd4 , epigenetics , chromatin , bet inhibitor , histone , histone acetyltransferase , transcription factor , transcription (linguistics) , biology , fragile x syndrome , genetics , neuroscience , gene , linguistics , philosophy
Bromodomain and extraterminal proteins (BET) are epigenetic readers that play critical roles in gene regulation. Pharmacologic inhibition of the bromodomain present in all BET family members is a promising therapeutic strategy for various diseases, but its impact on individual family members has not been well understood. Using a transcriptional induction paradigm in neurons, we have systematically demonstrated that three major BET family proteins (BRD2/3/4) participated in transcription with different recruitment kinetics, interdependency, and sensitivity to a bromodomain inhibitor, JQ1. In a mouse model of fragile X syndrome (FXS), BRD2/3 and BRD4 showed oppositely altered expression and chromatin binding, correlating with transcriptional dysregulation. Acute inhibition of CBP/p300 histone acetyltransferase (HAT) activity restored the altered binding patterns of BRD2 and BRD4 and rescued memory impairment in FXS. Our study emphasizes the importance of understanding the BET coordination controlled by a balanced action between HATs with different substrate specificity.