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.
| Original language | English |
|---|---|
| Pages (from-to) | 84-98.e9 |
| Journal | Molecular Cell |
| Volume | 79 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 2 2020 |
Bibliographical note
Funding Information:We thank Dr. Andrew G. Elefanty for sharing the HES-3 NKX2-1 GFP/w human embryonic stem cell line, Dr. Stewart A. Anderson for sharing the cortical interneuron differentiation protocol, and Dr. Guilin Wang for Chromium service. I.-H.P. was partly supported by the NIH ( GM111667-01 , R01MH118344-01A1 , R01MH118554-01A1 , R01AA025080-01 , and R01CA203011-2 ), CSCRF ( 14-SCC-YALE-01 and 16-RMB-YALE-04 ), the Kavli Foundation , the Simons Foundation , the Nomis Foundation , and the KRIBB/KRCF Research Initiative Program ( NAP-09-3 ). This work was supported by the College of Medicine , University of Arkansas for Medical Sciences (to S.-H.L.) and Core Facilities of the Center for Translational Neuroscience award P30 GM110702 from the IDeA Program at NIGMS . G.J.S. was partly supported by the Norwegian Research Council through its Centres of Excellence funding scheme (project number 262613 ). Computation time was provided by the Yale University Biomedical High Performance Computing Center.
Funding Information:
We thank Dr. Andrew G. Elefanty for sharing the HES-3 NKX2-1GFP/w human embryonic stem cell line, Dr. Stewart A. Anderson for sharing the cortical interneuron differentiation protocol, and Dr. Guilin Wang for Chromium service. I.-H.P. was partly supported by the NIH (GM111667-01, R01MH118344-01A1, R01MH118554-01A1, R01AA025080-01, and R01CA203011-2), CSCRF (14-SCC-YALE-01 and 16-RMB-YALE-04), the Kavli Foundation, the Simons Foundation, the Nomis Foundation, and the KRIBB/KRCF Research Initiative Program (NAP-09-3). This work was supported by the College of Medicine, University of Arkansas for Medical Sciences (to S.-H.L.) and Core Facilities of the Center for Translational Neuroscience award P30 GM110702 from the IDeA Program at NIGMS. G.J.S. was partly supported by the Norwegian Research Council through its Centres of Excellence funding scheme (project number 262613). Computation time was provided by the Yale University Biomedical High Performance Computing Center. Y.X. and I.-H.P. conceived the study. Y.X. performed the experiments. Y.T. performed ChIP-seq and analysis of all sequencing datasets. Y.X. and B.P. prepared samples for scRNA-seq. B.P. performed Hi-C. S.-M.H. Y.-J.K. E.M.C. and S.-H.L. performed patch-clamp recordings. E.H. performed RRBS and oxRRBS. B.C. K.-Y.K. and W.W. performed cell culture. Y.S.C. G.J.S. P.P. S.M.W. and M.Z. coordinated and performed deep sequencing. Y.X. Y.T. and I.-H.P. wrote the manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2020 Elsevier Inc.
Keywords
- BRD4
- JQ1
- MeCP2
- Rett syndrome
- brain organoid
- interneuron
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology