Interaction of Methyl-CpG-binding Protein 2 (MeCP2) with Distinct Enhancers in the Mouse Cortex

Overview

Journal Nat Neurosci

Date 2024 Nov 23

PMID 39578572

Authors

Gyan Prakash Mishra

Eric X Sun

Tiffany Chin

Mandy Eckhardt

Michael E Greenberg

Hume Stroud

Affiliations

Soon will be listed here.

Abstract

Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome. MeCP2 is thought to regulate gene transcription by binding to methylated DNA broadly across the genome. Here, using cleavage under target and release under nuclease (CUT&RUN) assays in the adult mouse cortex, we show that MeCP2 strongly binds to specific gene enhancers that we call MeCP2-binding hotspots (MBHs). Unexpectedly, we find that MeCP2 binding to MBHs occurs in a DNA methylation-independent manner at MBHs. Multiple MBH sites surrounding genes mediate the transcriptional repression of genes enriched for neuronal functions. We show that MBHs regulate genes irrespective of genic methylation levels, suggesting that MeCP2 controls transcription via an intragenic methylation-independent mechanism. Hence, disruption of intragenic methylation-independent gene regulation by MeCP2 may in part underlie Rett syndrome.

Citing Articles

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MeCP2 goes into unmethylated territories.

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