MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice.
MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice.
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DOI：
10.1038/mp.2016.254
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发表时间：
2018-01
影响因子：
11
通讯作者：
Akbarian S
中科院分区：
文献类型：
--
作者：
Mitchell AC;Javidfar B;Pothula V;Ibi D;Shen EY;Peter CJ;Bicks LK;Fehr T;Jiang Y;Brennand KJ;Neve RL;Gonzalez-Maeso J;Akbarian S
绘制精神分裂症基因组风险架构的大规模联盟提供了大量分子信息，其治疗潜力在很大程度上尚未开发。我们利用精神病学基因组学联盟的公开信息，报告了风险位点内得分最高的单核苷酸多态性周围序列中的心肌细胞增强因子 2C (MEF2C) 基序富集，这些序列因个体对疾病遗传性的影响较小而富集。对从 34 名受试者（包括 17 名诊断为精神分裂症的病例）的前额皮质中提取的神经元核小体进行碱基对分辨率 (ChIP-seq) 染色质分析，揭示了顺式调控序列中的 MEF2C 基序富集，包括神经元特异性启动子和超级增强子，在疾病病例中受到组蛋白 H3K4 高甲基化的影响。载体诱导的小鼠前额叶投射神经元中的短期和长期 Mef2c 上调始终导致基线和致精神病性药物挑战后工作记忆和物体识别范式的认知性能增强，并结合局部连接的重塑。 Mef2c-Dam 腺嘌呤甲基转移酶融合蛋白在体内进行的神经元基因组标记证实了认知增强与 MEF2C 占据包含典型和变异 MEF2C 基序的启动子之间的联系。这里提出的多层综合方法提供了一个路线图，以揭示转录调节因子对精神分裂症和相关疾病的治疗潜力。
Large scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report MYOCYTE ENHANCER FACTOR 2C (MEF2C) motif enrichment in sequences surrounding the top scoring single nucleotide polymorphisms within risk loci contributing by individual small effect to disease heritability. Chromatin profiling at base pair resolution (ChIP-seq) in neuronal nucleosomes extracted from prefrontal cortex of 34 subjects, including 17 cases diagnosed with schizophrenia, revealed MEF2C motif enrichment within cis-regulatory sequences, including neuron-specific promoters and superenhancers, affected by histone H3K4 hypermethylation in disease cases. Vector-induced short- and long-term Mef2c upregulation in mouse prefrontal projection neurons consistently resulted in enhanced cognitive performance in working memory and object recognition paradigms at baseline and after psychotogenic drug challenge, in conjunction with remodeling of local connectivity. Neuronal genome tagging in vivo by Mef2c-Dam adenine methyltransferase fusion protein confirmed the link between cognitive enhancement and MEF2C occupancy at promoters harboring canonical and variant MEF2C motifs. The multilayered integrative approaches presented here provide a roadmap to uncover the therapeutic potential of transcriptional regulators for schizophrenia and related disorders.
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影响因子：
16.2
作者：
Flavell, Steven W.;Kim, Tae-Kyung;Gray, Jesse M.;Harmin, David A.;Hemberg, Martin;Hong, Elizabeth J.;Markenscoff-Papadimitriou, Eirene;Bear, Daniel M.;Greenberg, Michael E.
通讯作者：
Greenberg, Michael E.
影响因子：
14.9
作者：
Goujon M;McWilliam H;Li W;Valentin F;Squizzato S;Paern J;Lopez R
通讯作者：
Lopez R
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
3.7
作者：
Dong X;Tsuji J;Labadorf A;Roussos P;Chen JF;Myers RH;Akbarian S;Weng Z
通讯作者：
Weng Z
甲基苯丙胺相关的记忆受作者和允许组蛋白甲基化的橡皮擦调节。
影响因子：
10.6
作者：
Aguilar-Valles, Argel;Vaissiere, Thomas;Griggs, Erica M.;Mikaelsson, Mikael A.;Takacs, Irma F.;Young, Erica J.;Rumbaugh, Gavin;Miller, Courtney A.
通讯作者：
Miller, Courtney A.