MeCP2 is required for global heterochromatic and nucleolar changes during activity-dependent neuronal maturation

Malaika K. Singleton, Michael L. Gonzales, Karen N. Leung, Dag H. Yasui, Diane I. Schroeder, Keith Dunaway, Janine M LaSalle

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Mutations in MECP2, encoding methyl CpG binding protein 2, cause the neurodevelopmental disorder Rett syndrome. MeCP2 is an abundant nuclear protein that binds to chromatin and modulates transcription in response to neuronal activity. Prior studies of MeCP2 function have focused on specific gene targets of MeCP2, but a more global role for MeCP2 in neuronal nuclear maturation has remained unexplored. MeCP2 levels increase during postnatal brain development, coinciding with dynamic changes in neuronal chromatin architecture, particularly detectable as changes in size, number, and location of nucleoli and perinucleolar heterochromatic chromocenters. To determine a potential role for MeCP2 in neuronal chromatin maturational changes, we measured nucleoli and chromocenters in developing wild-type and Mecp2-deficient mouse cortical sections, as well as mouse primary cortical neurons and a human neuronal cell line following induced maturation. Mecp2-deficient mouse neurons exhibited significant differences in nucleolar and chromocenter number and size, as more abundant, smaller nucleoli in brain and primary neurons compared to wild-type, consistent with delayed neuronal nuclear maturation in the absence of MeCP2. Primary neurons increased chromocenter size following depolarization in wild-type, but not Mecp2-deficient cultures. Wild-type MECP2e1 over-expression in human SH-SY5Y cells was sufficient to induce significantly larger nucleoli, but not a T158M mutation of the methyl-binding domain. These results suggest that, in addition to the established role of MeCP2 in transcriptional regulation of specific target genes, the global chromatin-binding function of MeCP2 is essential for activity-dependent global chromatin dynamics during postnatal neuronal maturation.

Original languageEnglish (US)
Pages (from-to)190-200
Number of pages11
JournalNeurobiology of Disease
Volume43
Issue number1
DOIs
StatePublished - Jul 2011

Fingerprint

Chromatin
Neurons
Methyl-CpG-Binding Protein 2
Rett Syndrome
Mutation
Brain
Nuclear Proteins
Genes
Cell Line

Keywords

  • Chromatin
  • DNA methylation
  • Epigenetic
  • Maturation
  • MeCP2
  • Neurodevelopmental
  • Neuronal
  • Nucleoli
  • Rett syndrome

ASJC Scopus subject areas

  • Neurology

Cite this

MeCP2 is required for global heterochromatic and nucleolar changes during activity-dependent neuronal maturation. / Singleton, Malaika K.; Gonzales, Michael L.; Leung, Karen N.; Yasui, Dag H.; Schroeder, Diane I.; Dunaway, Keith; LaSalle, Janine M.

In: Neurobiology of Disease, Vol. 43, No. 1, 07.2011, p. 190-200.

Research output: Contribution to journalArticle

Singleton, Malaika K. ; Gonzales, Michael L. ; Leung, Karen N. ; Yasui, Dag H. ; Schroeder, Diane I. ; Dunaway, Keith ; LaSalle, Janine M. / MeCP2 is required for global heterochromatic and nucleolar changes during activity-dependent neuronal maturation. In: Neurobiology of Disease. 2011 ; Vol. 43, No. 1. pp. 190-200.
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