MeCP2 represses the rate of transcriptional initiation of highly methylated long genes (HiC)

Mutations in the methyl-DNA-binding repressor protein MeCP2 cause the devastating neurodevelopmental disorder Rett syndrome. It has been challenging to understand how MeCP2 regulates transcription because MeCP2 binds broadly across the genome, and MeCP2 mutations are associated with widespread small-magnitude changes in neuronal gene expression. We demonstrate here that MeCP2 represses nascent RNA transcription of highly methylated long genes in the brain through its interaction with the NCoR co-repressor complex. By measuring the rates of transcriptional initiation and elongation directly in the brain, we find that MeCP2 has no measurable effect on transcriptional elongation, but instead represses the rate at which Pol II initiates transcription of highly methylated long genes. These findings suggest a new model of MeCP2 function in which MeCP2 binds broadly across highly methylated regions of DNA, but acts at transcription start sites to attenuate transcriptional initiation. Overall design: Hi-C was performed from forebrain tissue from 3 WT and 3 MeCP2 KO mice.

甲基化DNA结合阻遏蛋白MeCP2（methyl-DNA-binding repressor protein MeCP2）的突变会引发毁灭性的神经发育障碍瑞特综合征（Rett syndrome）。此前，阐明MeCP2调控转录的机制颇具挑战：一方面MeCP2可广泛结合于基因组各处，另一方面其突变与神经元基因表达中广泛存在的小幅变化相关。本研究证实，大脑内的MeCP2可通过与NCoR辅阻遏复合物（NCoR co-repressor complex）相互作用，抑制高度甲基化长基因的新生RNA转录。通过直接检测大脑内转录起始与延伸的速率，我们发现MeCP2对转录延伸无显著可检测的影响，反而会抑制高度甲基化长基因的RNA聚合酶II（Pol II）的转录起始速率。上述研究结果提出了一种全新的MeCP2功能模型：MeCP2广泛结合于高度甲基化的DNA区域，却仅在转录起始位点发挥作用，以减弱转录起始过程。整体实验设计：对3只野生型（WT）小鼠和3只MeCP2基因敲除（KO）小鼠的前脑组织开展Hi-C实验。