Acute MeCP2 Loss in Adult Mice Reveals Transcriptional and Chromatin Changes That Precede Neurological Dysfunction and Inform Pathogenesis

Authors

Sameer S Bajikar
Jian Zhou
Ryan O'Hara
Harini P Tirumala
Mark A Durham
Alexander J Trostle
Michelle Dias
Yingyao Shao
Hu Chen
Wei Wang
Hari Krishna Yalamanchili
Ying-Wooi Wan
Laura A Banaszynski
Zhandong Liu
Huda Y Zoghbi

Publication Date

2-5-2025

Journal

Neuron

DOI

10.1016/j.neuron.2024.11.006

PMID

39689710

PMCID

PMC11802321

PubMedCentral® Posted Date

2-5-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Methyl-CpG-Binding Protein 2, Chromatin, Mice, Hippocampus, Rett Syndrome, Histones, Male, Mice, Knockout, Mice, Inbred C57BL, Transcription, Genetic, Transcriptome, Acetylation

Abstract

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis. We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome. To understand what drives gene downregulation, we profiled genome-wide histone modifications and found that a decrease in histone H3 acetylation (ac) at downregulated genes is among the earliest molecular changes occurring well before any measurable deficiencies in electrophysiology and neurological function. These data reveal a molecular cascade that drives disease independent of any developmental contributions or secondary pathogenesis.