Dysregulation of BRD4 function underlies the functional abnormalities of MeCP2 mutant neurons

Cited 32 time in scopus
Metadata Downloads
Title
Dysregulation of BRD4 function underlies the functional abnormalities of MeCP2 mutant neurons
Author(s)
Y Xiang; Y Tanaka; B Patterson; S M Hwang; E Hysolli; B Cakir; K Y Kim; W Wang; Y J Kang; E m Clement; M Zhong; S H Lee; Yee Sook Cho; P Patra; G J Sullivan; S M Weissman; I Y Park
Bibliographic Citation
Molecular Cell, vol. 79, no. 1, pp. 84-98
Publication Year
2020
Abstract
Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT.
Keyword
BRD4JQ1MeCP2Rett syndromeBrain organoidInterneuron.
ISSN
1097-2765
Publisher
Elsevier-Cell Press
DOI
http://dx.doi.org/10.1016/j.molcel.2020.05.016
Type
Article
Appears in Collections:
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.