Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates
Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates
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DOI：
10.1038/nature21722
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发表时间：
2017-04-13
期刊：
影响因子：
64.8
通讯作者：
Wernig, Marius
中科院分区：
文献类型：
--
作者：
Mall, Moritz;Kareta, Michael S.;Wernig, Marius
正常分化和诱导重编程需要激活靶细胞程序和沉默供体细胞程序（1,2）。在重编程中，通常使用相同的因子对许多不同的供体细胞类型进行重编程。由于大多数发育抑制因子，如re1沉默转录因子（REST）和Groucho（也称为TLE），被认为是谱系特异性抑制因子（4,5），目前尚不清楚相同的转录因子组合如何能够沉默如此多不同的供体程序。不同的谱系抑制因子必须在不同的供体细胞类型中被诱导。在这里，通过研究小鼠成纤维细胞向神经元的重编程，我们发现泛神经元特异性转录因子Myt1-like (Myt1l)(6)通过直接抑制除神经元程序外的许多不同的体细胞谱系程序来发挥其前神经元功能。Myt1l的抑制功能是通过结合先前未表征的n端结构域募集含有Sin3b的复合物来介导的。与其抑制功能一致，Myt1l的基因组结合位点在神经元和成纤维细胞中是相似的，并且优先处于开放的染色质结构中。myt11通过沉默包括Hes1在内的几个成员来抑制Notch信号通路。发育中的小鼠大脑中Myt1l的急性敲低模拟了Notch功能获得表型，这表明Myt1l允许新生神经元在正常发育过程中逃避Notch激活。Myt1l在原发性有丝分裂后神经元中的缺失会抑制非神经元程序，损害神经元基因的表达和功能，这表明许多体细胞谱系程序被Myt1l积极和持续地抑制，以维持神经元的身份。现在人们很容易推测，类似的“多合一”谱系抑制因子存在于其他细胞命运中；这些抑制因子，结合谱系特异性激活因子，将是用于重编程其他细胞类型的主要候选者。
Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs(1,2). In reprogramming, the same factors are often used to reprogram many different donor cell types3. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors(4,5), it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l)(6) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.