Dynamic changes in histone H3 lysine 9 acetylation localization patterns during neuronal maturation require Mecp2

Karen N. Thatcher, Janine M LaSalle

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Mutations within the gene encoding methyl CpG binding protein 2 (MECP2) cause the autism-spectrum neurodevelopmental disorder Rett Syndrome (RTT). MeCP2 recruits histone deacetylase to methylated DNA and acts as a long-range regulator of methylated genes. Despite ubiquitous MECP2 expression, the phenotype of RTT and the Mecp2-deficient mouse is largely restricted to the post-natal brain. Since Mecp2-deficient mice have a defect in neuronal maturation, we sought to understand how MECP2/Mecp2 mutations globally affect histone modifications during post-natal brain development by an immunofluorescence approach. Using an antibody specific to acetylated histone H3 lysine 9 (H3K9ac), a bright punctate nuclear staining pattern was observed as MECP2 expression increased in early post-natal neuronal nuclei. As neurons matured in juvenile and adult brain samples, the intensity of H3K9ac staining was reduced. Mecp2-deficient mouse and RTT cerebral neurons lacked this developmental reduction in H3K9ac staining compared to age-matched controls, resulting in a significant increase in neuronal nuclei with bright H3K9ac punctate staining. In contrast, trimethylated histone H3 lysine 9 (H3K9me3) localized to heterochromatin independent of Mecp3, but showed significantly reduced levels in Mecp2 deficient mouse and RTT brain. Autism brain with reduced MECP2 expression displayed similar histone H3 alterations as RTT human brain. These observations suggest that MeCP2 regulates global histone modifications during a critical post-natal stage of neuronal maturation. These results have implications for understanding the molecular pathogenesis of RTT and autism in which MECP2 mutation or deficiency corresponds with arrested neurodevelopment.

Original languageEnglish (US)
Pages (from-to)24-31
Number of pages8
JournalEpigenetics
Volume1
Issue number1
DOIs
StatePublished - 2006

Keywords

  • Acetylation
  • Autism
  • Brain
  • Histone
  • MeCP2
  • Methylation
  • Neuron
  • Rett syndrome

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Medicine(all)

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