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Mecp2: an unexpected regulator of macrophage gene expression and function [ChIP-Seq]

ABSTRACT: Mutations in methyl-CpG-binding protein 2 (MeCP2), a major epigenetic regulator, are the predominant cause of Rett syndrome. We previously found that Mecp2-null microglia are deficient in phagocytic ability, and that engraftment of wild-type monocytes into the brain of Mecp2-deficient mice attenuates pathology. We have observed that Mecp2 deficiency is associated with increased levels of histone acetylation at the cis-regulatory regions of the Mecp2-regulated genes in macrophages. We hypothesized that Mecp2 recruits protein complexes containing histone deacetylases (HDACs) to repress the expression of its target genes. Our ChIP-Seq studies in bone-marrow derived macrophages revealed that Mecp2 co-localizes with Ncor2/Hdac3 protein complex at cis-regulatory regions of the target genes. These results suggest a role for Mecp2 in the recruitment and regulation of Ncor2/Hdac3 repressosome that plays a critical role in the regulation of inflammatory responses in macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE66501 | GEO | 2015/03/31

SECONDARY ACCESSION(S): PRJNA277172

REPOSITORIES: GEO

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Project description:Mutations in methyl-CpG-binding protein 2 (MeCP2), a major epigenetic regulator, are the predominant cause of Rett syndrome, an X-linked neurodevelopmental disorder. We previously found that Mecp2-null microglia are functionally impaired, and that engraftment of wild-type monocytes into the brain of Mecp2-deficient mice attenuates pathology. In this study we show that Mecp2 is expressed in macrophage and monocyte populations throughout the body, and is indispensable for their transcriptional regulation in multiple contexts. We demonstrate that Mecp2-null mice progressively lose or are chronically deficient in several macrophage populations and resident monocytes. Postnatal re-expression of Mecp2 driven by a tamoxifen-inducible CX3CR1 promoter significantly increased the lifespan of otherwise Mecp2-null mice, suggesting that epigenetic regulation of macrophage function by Mecp2 significantly contributes to pathology. RNA-Seq of acutely isolated microglia and peritoneal macrophages (to our knowledge, the first cell-specific RNA-Seq analysis comparing Mecp2-null and wild type cells of any kind) revealed significantly increased transcription of glucocorticoid- and hypoxia-signaling genes in Mecp2-null cells compared to that in their wild-type counterparts, suggesting that Mecp2 functions as a repressor of these pathways. Furthermore, in-vitro and in vivo validation studies demonstrated that the absence of Mecp2 is associated with cell-intrinsic dysfunction of signaling underlying inflammatory activation, suggesting that Mecp2 is important for regulation of specific macrophage gene-expression programs in response to stimuli and stressors. Our findings demonstrate a fundamental role for Mecp2 in the regulation of macrophage functions, which may provide a link to pathologies in Rett syndrome across multiple organs. Mecp2-null microglia and resident peritoneal macrophages from 10-12 week old mice were acutely isolated via AutoMACS, total RNA collected, and analyzed via RNA-Seq to compare for transcriptional differences in microglia and macrophages in the absence of Mecp2.

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Mecp2: an unexpected regulator of macrophage gene expression and function [ChIP-Seq]

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