MeCP2 represses the rate of transcriptional initiation of highly methylated long genes (ChIP-Seq II)

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: ChIP-seq was performed from WT and MeCP2 KO forebrain for H3K36me3 (n=10), H3K27ac (n=10), MeCP2 Ab1 (n=2), MeCP2 Ab2 (n=2), and pre-immune serum for MeCP2 Ab1 (n=2) with input controls. ChIP-seq was performed from WT and MeCP2 R306C forebrain for H3K9ac (n=5), H3K27ac (n=2), H4K12ac (n=3), and MeCP2 (n=4) with input controls. ChIP-seq was peformed from WT cortical neurons for YY1, and from WT forebrain for H3K79me2 (n=2) with input controls.