In vitro studies indicate the neurodevelopmental disorder gene myelin transcription factor 1-like (MYT1L) suppresses non-neuronal lineage genes during fibroblast-to-neuron direct differentiation. However, MYT1L's molecular and cellular functions in the adult mammalian brain have not been fully characterized. Here, we found that MYT1L loss leads to up-regulated deep layer (DL) gene expression, corresponding to an increased ratio of DL/UL neurons in the adult mouse cortex. To define potential mechanisms, we conducted Cleavage Under Targets & Release Using Nuclease (CUT&RUN) to map MYT1L binding targets and epigenetic changes following MYT1L loss in mouse developing cortex and adult prefrontal cortex (PFC). We found MYT1L mainly binds to open chromatin, but with different transcription factor co-occupancies between promoters and enhancers. Likewise, multiomic data set integration revealed that, at promoters, MYT1L loss does not change chromatin accessibility but increases H3K4me3 and H3K27ac, activating both a subset of earlier neuronal development genes as well as Bcl11b, a key regulator for DL neuron development. Meanwhile, we discovered that MYT1L normally represses the activity of neurogenic enhancers associated with neuronal migration and neuronal projection development by closing chromatin structures and promoting removal of active histone marks. Further, we showed that MYT1L interacts with HDAC2 and transcriptional repressor SIN3B in vivo, providing potential mechanisms underlying repressive effects on histone acetylation and gene expression. Overall, our findings provide a comprehensive map of MYT1L binding in vivo and mechanistic insights into how MYT1L loss leads to aberrant activation of earlier neuronal development programs in the adult mouse brain.

中文翻译：

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MYT1L 是抑制成年小鼠大脑早期神经元发育程序所必需的


体外研究表明，神经发育障碍基因髓磷脂转录因子 1 样 (MYT1L) 在成纤维细胞向神经元直接分化过程中抑制非神经元谱系基因。然而，MYT1L 在成年哺乳动物大脑中的分子和细胞功能尚未得到充分表征。在这里，我们发现 MYT1L 缺失导致深层 (DL) 基因表达上调，对应于成年小鼠皮质中 DL/UL 神经元比例的增加。为了确定潜在的机制，我们进行了使用核酸酶进行目标切割和释放 (CUT&RUN)，以绘制 MYT1L 结合目标以及小鼠发育皮层和成人前额叶皮层 (PFC) 中 MYT1L 丢失后的表观遗传变化。我们发现 MYT1L 主要与开放染色质结合，但启动子和增强子之间具有不同的转录因子共占用。同样，多组学数据集整合显示，在启动子处，MYT1L 丢失不会改变染色质可及性，但会增加 H3K4me3 和 H3K27ac，从而激活早期神经元发育基因的子集以及 DL 神经元发育的关键调节因子Bcl11b 。同时，我们发现MYT1L通常通过关闭染色质结构和促进活性组蛋白标记的去除来抑制与神经元迁移和神经元投射发育相关的神经源性增强子的活性。此外，我们还发现 MYT1L 在体内与 HDAC2 和转录抑制因子 SIN3B 相互作用，提供了对组蛋白乙酰化和基因表达抑制作用的潜在机制。 总的来说，我们的研究结果提供了 MYT1L 体内结合的全面图谱，以及 MYT1L 缺失如何导致成年小鼠大脑中早期神经元发育程序异常激活的机制见解。