KMT2B Is Selectively Required for Neuronal Transdifferentiation, and Its Loss Exposes Dystonia Candidate Genes.
KMT2B Is Selectively Required for Neuronal Transdifferentiation, and Its Loss Exposes Dystonia Candidate Genes.
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DOI：
10.1016/j.celrep.2018.09.067
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发表时间：
2018-10-23
期刊：
影响因子：
8.8
通讯作者：
Testa G
中科院分区：
文献类型：
--
作者：
Barbagiovanni G;Germain PL;Zech M;Atashpaz S;Lo Riso P;D'Antonio-Chronowska A;Tenderini E;Caiazzo M;Boesch S;Jech R;Haslinger B;Broccoli V;Stewart AF;Winkelmann J;Testa G
神经特异性转录因子Brn2、Myt1l和Ascl1将成纤维细胞转分化为诱导神经细胞（iNs），这是表观遗传距离较远的细胞间谱系转换的典型例子。尽管在转分化背后的转录层次方面取得了巨大进展，但伴随的表观基因组重置的使能因素仍有待阐明。在这里，我们研究了KMT2A和KMT2B，两种组蛋白H3赖氨酸4甲基化酶在发育中起主要作用，通过单独和联合失活。我们发现Kmt2b，其人类同源基因的突变导致肌张力障碍，是选择性地通过抑制替代肌细胞程序和诱导神经元成熟基因进行iN转换所必需的。KMT2B易感靶点的鉴定反过来使我们能够在225名患者的队列中发现39个KMT2B靶点中的45个独特变体，这些靶点代表了解剖肌张力障碍分子基础的有希望的候选者。KMT2B对神经元转分化至关重要，而KMT2A则是可有可无的。KMT2B负责神经元成熟基因程序的激活。KMT2B抑制转分化缺陷时释放的肌细胞命运。KMT2B依赖性揭示了肌张力障碍的候选致病基因。Barbagiovanni等人证明，与KMT2A相比，KMT2B是成纤维细胞转分化为诱导神经细胞（iNs）的表观遗传和转录组重置的基础，在抑制替代命运和促进in成熟中起作用。转分化特异性KMT2B靶点揭示肌张力障碍致病基因候选物。
Transdifferentiation of fibroblasts into induced neuronal cells (iNs) by the neuron-specific transcription factors Brn2, Myt1l, and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress regarding the transcriptional hierarchy underlying transdifferentiation, the enablers of the concomitant epigenome resetting remain to be elucidated. Here, we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and combined inactivation. We found that Kmt2b, whose human homolog’s mutations cause dystonia, is selectively required for iN conversion through suppression of the alternative myocyte program and induction of neuronal maturation genes. The identification of KMT2B-vulnerable targets allowed us, in turn, to expose, in a cohort of 225 patients, 45 unique variants in 39 KMT2B targets, which represent promising candidates to dissect the molecular bases of dystonia. KMT2B is critical for neuronal transdifferentiation, whereas KMT2A is dispensable KMT2B is responsible for the activation of the neuronal maturation gene program KMT2B represses the myocyte fate unleashed upon defective transdifferentiation KMT2B dependence reveals candidate dystonia-causative genes Barbagiovanni et al. demonstrate that KMT2B, in contrast to KMT2A, is fundamental for the epigenetic and transcriptomic resetting underlying transdifferentiation of fibroblasts into induced neuronal cells (iNs), acting both in the suppression of alternative fates and in the promotion of iN maturation. Transdifferentiation-specific KMT2B targets reveal dystonia-causative gene candidates.
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影响因子：
23.9
作者：
Hörmanseder E;Simeone A;Allen GE;Bradshaw CR;Figlmüller M;Gurdon J;Jullien J
通讯作者：
Jullien J
影响因子：
8.8
作者：
Wapinski OL;Lee QY;Chen AC;Li R;Corces MR;Ang CE;Treutlein B;Xiang C;Baubet V;Suchy FP;Sankar V;Sim S;Quake SR;Dahmane N;Wernig M;Chang HY
通讯作者：
Chang HY
影响因子：
--
作者：
Strom SP;Lozano R;Lee H;Dorrani N;Mann J;O'Lague PF;Mans N;Deignan JL;Vilain E;Nelson SF;Grody WW;Quintero-Rivera F
通讯作者：
Quintero-Rivera F
通过确定的因素将成纤维细胞直接转化为功能性神经元。
影响因子：
64.8
作者：
Vierbuchen, Thomas;Ostermeier, Austin;Pang, Zhiping P.;Kokubu, Yuko;Suedhof, Thomas C.;Wernig, Marius
通讯作者：
Wernig, Marius
影响因子：
64.5
作者：
Wapinski OL;Vierbuchen T;Qu K;Lee QY;Chanda S;Fuentes DR;Giresi PG;Ng YH;Marro S;Neff NF;Drechsel D;Martynoga B;Castro DS;Webb AE;Südhof TC;Brunet A;Guillemot F;Chang HY;Wernig M
通讯作者：
Wernig M