MYT1L is required for suppressing earlier neuronal development programs in the adult mouse brain.
MYT1L is required for suppressing earlier neuronal development programs in the adult mouse brain.
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DOI：
10.1101/gr.277413.122
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发表时间：
2023-04
期刊：
影响因子：
7
通讯作者：
Dougherty, Joseph D
中科院分区：
文献类型：
--
作者：
Chen, Jiayang;Fuhler, Nicole A;Noguchi, Kevin K;Dougherty, Joseph D
体外研究表明，神经发育障碍基因髓磷脂转录因子1样（MYT 1 L）抑制成纤维细胞向神经元直接分化过程中的非神经元谱系基因。然而，MYT 1 L在成年哺乳动物大脑中的分子和细胞功能尚未完全表征。在这里，我们发现MYT 1 L损失导致上调深层（DL）基因表达，对应于成年小鼠皮层中DL/UL神经元的比例增加。为了确定潜在的机制，我们进行了靶下切割和使用核酸酶释放（CUT&RUN），以绘制小鼠发育皮层和成年前额叶皮层（PFC）中MYT 1 L丢失后MYT 1 L结合靶点和表观遗传变化。我们发现MYT 1 L主要与开放染色质结合，但在启动子和增强子之间存在不同的转录因子。同样，多组数据集整合显示，在启动子处，MYT 1 L丢失不会改变染色质可及性，但会增加H3 K4 me 3和H3 K27 ac，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Bcl 11b。同时，我们发现MYT 1 L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原性增强子的活性。此外，我们发现MYT 1 L在体内与HDAC 2和转录抑制因子SIN 3B相互作用，提供了抑制组蛋白乙酰化和基因表达的潜在机制。总的来说，我们的研究结果提供了一个全面的地图MYT 1 L结合在体内和机制的见解MYT 1 L损失如何导致异常激活的早期神经元发育程序在成年小鼠大脑。
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.