Free as a BRD4: Bromodomain Inhibition Ameliorates Disease Phenotypes in a Model of MECP2 Deficiency and Is a Potential Therapy for Rett Syndrome.
Free as a BRD4: Bromodomain Inhibition Ameliorates Disease Phenotypes in a Model of MECP2 Deficiency and Is a Potential Therapy for Rett Syndrome.
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DOI：
10.1177/1535759720960469
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发表时间：
2020-11
影响因子：
3.6
通讯作者：
Carvill GL
中科院分区：
文献类型：
--
作者：
Lamar KJ;Carvill GL
BRD 4功能失调是MeCP 2突变神经元功能缺失的基础Xiang Y，Tanaka Y，Patterson B，et al. Mole Cell. 2020;79（1）：84-98. e9. doi：10.1016/j.molcel.2020.05.016 Rett综合征（RTT）主要由甲基-CpG结合蛋白2（MeCP 2）突变引起，是最常见的智力障碍之一，目前尚无有效的治疗方法。在这里，我们使用2D和3D人脑培养来研究MeCP 2功能。我们发现MeCP 2突变导致人类中间神经元（IN）严重异常。令人惊讶的是，用BET抑制剂JQ 1治疗，挽救了MeCP 2突变INs. We发现，BRD 4的染色质结合和增强子-启动子相互作用的异常增加是MeCP 2突变INs异常转录的基础，JQ 1将其恢复到正常水平。我们揭示了被JQ 1拯救的MeCP 2突变区域特异性人脑类器官中的细胞类型特异性转录组损伤。最后，JQ 1改善了小鼠的RTT样表型。这些数据表明，BRD 4失调是RTT病因学的关键驱动因素，并表明靶向BRD 4可能是RTT的潜在治疗机会。
Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons Xiang Y, Tanaka Y, Patterson B, et al. Mole Cell. 2020;79(1):84-98. e9. doi:10.1016/j.molcel.2020.05.016 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.
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影响因子：
8.8
作者：
Bar, Shiran;Seaton, Lev Roz;Benvenisty, Nissim
通讯作者：
Benvenisty, Nissim
影响因子：
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Qian X;Nguyen HN;Song MM;Hadiono C;Ogden SC;Hammack C;Yao B;Hamersky GR;Jacob F;Zhong C;Yoon KJ;Jeang W;Lin L;Li Y;Thakor J;Berg DA;Zhang C;Kang E;Chickering M;Nauen D;Ho CY;Wen Z;Christian KM;Shi PY;Maher BJ;Wu H;Jin P;Tang H;Song H;Ming GL
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Ming GL
DOI：
10.2174/1871527315666160413120156
发表时间：
2016-01-01
影响因子：
3
作者：
Andoh-Noda, Tomoko;Inouye, Michiko O.;Akamatsu, Wado
通讯作者：
Akamatsu, Wado
DOI：
10.1002/ajmg.b.32707
发表时间：
2019-01-01
影响因子：
2.8
作者：
Neul, Jeffrey L.;Benke, Timothy A.;Percy, Alan K.
通讯作者：
Percy, Alan K.
DOI：
10.1126/science.aav5386
发表时间：
2019-12-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Sun AX;Yuan Q;Fukuda M;Yu W;Yan H;Lim GGY;Nai MH;D'Agostino GA;Tran HD;Itahana Y;Wang D;Lokman H;Itahana K;Lim SWL;Tang J;Chang YY;Zhang M;Cook SA;Rackham OJL;Lim CT;Tan EK;Ng HH;Lim KL;Jiang YH;Je HS
通讯作者：
Je HS