Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function.
Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function.
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DOI：
10.1016/j.neuron.2011.08.022
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发表时间：
2011-10-06
期刊：
影响因子：
16.2
通讯作者：
Greenberg ME
中科院分区：
文献类型：
--
作者：
Cohen S;Gabel HW;Hemberg M;Hutchinson AN;Sadacca LA;Ebert DH;Harmin DA;Greenberg RS;Verdine VK;Zhou Z;Wetsel WC;West AE;Greenberg ME
自闭症谱系障碍，如雷特综合征（RTT）已被假设为产生的缺陷，在经验依赖性突触成熟。RTT是由MECP 2突变引起的，MECP 2是一种核蛋白，响应于神经元激活而在S421处磷酸化。我们在这里表明，在体内的MeCP 2 S421磷酸化的破坏导致突触发育和行为的缺陷，暗示在脑发育和RTT的MeCP 2的活动依赖性调节。我们研究了S421磷酸化调节MeCP 2功能的机制，并通过染色质免疫沉淀测序显示这种修饰发生在整个基因组结合的MeCP 2上。MeCP 2 S421的磷酸化似乎不调节特定基因的表达;相反，MeCP 2作为组蛋白样因子发挥作用，其磷酸化可能促进神经系统发育期间染色质对神经元活性的全基因组响应。我们建议，RTT的结果部分从这种经验依赖性染色质重塑的损失。
Autism spectrum disorders such as Rett syndrome (RTT) have been hypothesized to arise from defects in experience-dependent synapse maturation. RTT is caused by mutations in MECP2, a nuclear protein that becomes phosphorylated at S421 in response to neuronal activation. We show here that disruption of MeCP2 S421 phosphorylation in vivo results in defects in synapse development and behavior, implicating activity-dependent regulation of MeCP2 in brain development and RTT. We investigated the mechanism by which S421 phosphorylation regulates MeCP2 function and show by chromatin immunoprecipitation-sequencing that this modification occurs on MeCP2 bound across the genome. The phosphorylation of MeCP2 S421 appears not to regulate the expression of specific genes; rather, MeCP2 functions as a histone-like factor whose phosphorylation may facilitate a genome-wide response of chromatin to neuronal activity during nervous system development. We propose that RTT results in part from a loss of this experience-dependent chromatin remodeling.
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影响因子：
25
作者：
Ballas, Nurit;Lioy, Daniel T.;Grunseich, Christopher;Mandel, Gail
通讯作者：
Mandel, Gail
影响因子：
64.8
作者：
Lin, Yingxi;Bloodgood, Brenda L.;Hauser, Jessica L.;Lapan, Ariya D.;Koon, Alex C.;Kim, Tae-Kyung;Hu, Linda S.;Malik, Athar N.;Greenberg, Michael E.
通讯作者：
Greenberg, Michael E.
影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
影响因子：
3.5
作者：
Collins, AL;Levenson, JM;Zoghbi, HY
通讯作者：
Zoghbi, HY
影响因子：
5.3
作者：
Maffei, Arianna;Turrigiano, Gina G.
通讯作者：
Turrigiano, Gina G.