Abstract
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.
Highlights
Bromodomain and extraterminal (BET) proteins are epigenetic readers that share two conserved bromodomains and one extraterminal (ET) domain [1, 2]
Our study demonstrated that individual BET proteins are recruited to the cis-regulatory regions with a hierarchical coordination
The chromatin binding profile in response to the inhibition of the BET bromodomain and CREB-binding protein (CBP)/p300 histone acetyltransferase (HAT) activity was widely varied among the family members, suggesting that the recruitment of each BET family member was mediated by distinctive mechanisms
Summary
Bromodomain and extraterminal (BET) proteins are epigenetic readers that share two conserved bromodomains and one extraterminal (ET) domain [1, 2]. BET proteins play a key role in gene transcription through their interactions with chromatin and various transcription regulators [3,4,5]. All small-molecule inhibitors of BET proteins including JQ1 commonly target the bromodomain binding pocket [13, 15, 17, 19], but the majority of studies have suggested that dysregulation of BRD4 function is the primary effect of pharmacologic BET inhibition [5, 7, 11, 14,15,16, 18,19,20]. The functional distinctions among different BET family members at the molecular level are still poorly understood This subject would be important for the accurate evaluation of the therapeutic benefits of currently available BET inhibitors as well as the development of more selective drugs that might benefit clinical interventions in a range of diseases
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