Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons.

Molecular Cell
Yangfei XiangIn-Hyun Park

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.

Citations

Dec 29, 2020·Frontiers in Cell and Developmental Biology·Ana Rita GomesMaria Margarida Diogo
Jan 20, 2021·Nature Chemical Biology·Gabi SchutziusSusan Kirkland
Mar 20, 2021·Journal of Tissue Engineering·Moshe J WillnerKam W Leong
May 1, 2021·International Journal of Molecular Sciences·Ana Rita GomesMaria Margarida Diogo
Sep 14, 2021·Frontiers in Neuroscience·Florencia D HaaseWendy A Gold
Oct 27, 2021·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Yin LiangTao Wu
Jan 5, 2022·Cell Regeneration·Xiaoxiang LuYangfei Xiang

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