Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons.
Animals
Azepines
/ pharmacology
Brain
/ drug effects
Cell Cycle Proteins
/ genetics
Female
Human Embryonic Stem Cells
/ drug effects
Humans
Induced Pluripotent Stem Cells
/ drug effects
Interneurons
/ drug effects
Male
Methyl-CpG-Binding Protein 2
/ physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Phenotype
Rett Syndrome
/ drug therapy
Transcription Factors
/ genetics
Transcriptome
/ drug effects
Triazoles
/ pharmacology
BRD4
JQ1
MeCP2
Rett syndrome
brain organoid
interneuron
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
02 07 2020
02 07 2020
Historique:
received:
02
09
2019
revised:
04
03
2020
accepted:
12
05
2020
pubmed:
12
6
2020
medline:
25
8
2020
entrez:
12
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32526163
pii: S1097-2765(20)30317-8
doi: 10.1016/j.molcel.2020.05.016
pmc: PMC7375197
mid: NIHMS1597370
pii:
doi:
Substances chimiques
(+)-JQ1 compound
0
Azepines
0
BRD4 protein, human
0
Cell Cycle Proteins
0
Mecp2 protein, mouse
0
Methyl-CpG-Binding Protein 2
0
Transcription Factors
0
Triazoles
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
84-98.e9Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM111667
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM110702
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH118554
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007499
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH118344
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA025080
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA203011
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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