The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.
The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.
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自闭症相关的染色质修饰剂CHD8在人神经发育过程中调节其他自闭症风险基因。
DOI：
10.1038/ncomms7404
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发表时间：
2015-03-10
影响因子：
16.6
通讯作者：
Noonan, James P.
中科院分区：
文献类型：
--
作者：
Cotney, Justin;Muhle, Rebecca A.;Sanders, Stephan J.;Liu, Li;Willsey, A. Jeremy;Niu, Wei;Liu, Wenzhong;Klei, Lambertus;Lei, Jing;Yin, Jun;Reilly, Steven K.;Tebbenkamp, Andrew T.;Bichsel, Candace;Pletikos, Mihovil;Sestan, Nenad;Roeder, Kathryn;State, Matthew W.;Devlin, Bernie;Noonan, James P.
最近的研究表明，染色质修饰物与自闭症谱系障碍(ASD)有关，这是通过鉴定受影响个体中反复发生的功能丧失突变来实现的。ASD风险基因在人中胎皮质中共表达，表明ASD风险基因在神经发育过程中聚集在特定的调控网络中。为了阐明这样的网络，我们在人中胎脑、人神经干细胞(HNSCs)和胚胎小鼠皮质中识别了CHD8靶向的基因，CHD8是一种与ASD密切相关的铬结构域解旋酶。CHD8靶基因在人类和小鼠的神经发育中都强烈富含其他ASD危险基因，并在人类中胎儿皮质中汇聚在ASD相关的共表达网络中。CHD8在hNSCs中的敲除导致CHD8直接靶向的ASD风险基因的失调。将CHD8结合数据整合到ASD风险模型中可以改进风险基因的检测。这些结果表明，CHD8的丢失通过扰乱人类大脑发育过程中一个古老的基因调控网络而导致ASD。自闭症基因在胎儿中期皮质共表达网络中汇聚，染色质调节因子如CHD8与自闭症谱系障碍(ASD)的相关性越来越大。在这里，作者绘制了发育中大脑中的CHD8靶点，并发现CHD8在人类神经发育过程中直接调节其他ASD风险基因。
Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human midfetal cortex, suggesting that ASD risk genes converge in specific regulatory networks during neurodevelopment. To elucidate such networks, we identify genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex. CHD8 targets are strongly enriched for other ASD risk genes in both human and mouse neurodevelopment, and converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8. Integration of CHD8-binding data into ASD risk models improves detection of risk genes. These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development. Autism genes converge in midfetal cortical co-expression networks, and chromatin regulators such as CHD8 are increasingly associated with autism spectrum disorder (ASD). Here the authors map CHD8 targets in developing brain, and find that CHD8 directly regulates other ASD risk genes during human neurodevelopment.
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影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
16
作者：
Ishihara, Ko;Oshimura, Mitsuo;Nakao, Mitsuyoshi
通讯作者：
Nakao, Mitsuyoshi
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS