Early-life gene expression in neurons modulates lasting epigenetic states. [RNA-Seq]

In mammals during the early postnatal period the environment plays a critical role in promoting the final steps in neuronal development. While epigenetic factors are thought to contribute to this process, the underlying molecular mechanisms remain poorly understood. Here we show that in the brain during early life the DNA methyltransferase DNMT3A transiently binds across transcribed regions of lowly expressed genes, and its binding specifies the pattern of DNA methylation at CA sequences (mCA) within these genes. We find that DNMT3A occupancy and mCA deposition within the transcribed regions of genes is negatively regulated by gene transcription and may be modified by early-life experience. Once deposited, mCA is bound by the methyl-DNA-binding protein MECP2 and functions in a rheostat-like manner to fine-tune the cell type-specific transcription of genes that are critical for brain function. Indrops single nuclei RNA-seq on mouse corticies在哺乳动物出生后早期阶段，环境对于促进神经元发育的最终进程发挥着关键作用。尽管表观遗传（epigenetic）因素被认为参与了这一过程，但其背后的分子机制仍未完全阐明。本研究揭示，在生命早期的大脑中，DNA甲基转移酶（DNA methyltransferase, DNMT3A）会短暂结合低表达基因的转录区域，且其结合可确定这些基因内CA序列处的DNA甲基化修饰（mCA）模式。我们发现，基因转录区域内DNMT3A的结合丰度与mCA沉积水平会受到基因转录的负向调控，且可因生命早期的环境经历而发生改变。一旦mCA沉积完成，其会被甲基DNA结合蛋白（methyl-DNA-binding protein, MECP2）识别结合，并以变阻器式的调控方式精准调控对大脑功能至关重要的基因的细胞类型特异性转录。本研究基于小鼠皮层的inDrop单细胞核RNA测序（inDrop single nuclei RNA-seq）数据完成。