MeCP2 Dependent Heterochromatin Reorganization during Neural Differentiation of a Novel Mecp2-Deficient Embryonic Stem Cell Reporter Line

Bianca Bertulat, Maria Luigia de Bonis, Floriana Della Ragione, Anne Lehmkuhl, Manuela Milden, Christian Storm, K. Laurence Jost, Simona Scala, Brian Hendrich, Maurizio D'Esposito, M. Cristina Cardoso

Research output: Contribution to journalArticle

Abstract

The X-linked Mecp2 is a known interpreter of epigenetic information and mutated in Rett syndrome, a complex neurological disease. MeCP2 recruits HDAC complexes to chromatin thereby modulating gene expression and, importantly regulates higher order heterochromatin structure. To address the effects of MeCP2 deficiency on heterochromatin organization during neural differentiation, we developed a versatile model for stem cell in vitro differentiation. Therefore, we modified murine Mecp2 deficient (Mecp2-/y) embryonic stem cells to generate cells exhibiting green fluorescent protein expression upon neural differentiation. Subsequently, we quantitatively analyzed heterochromatin organization during neural differentiation in wild type and in Mecp2 deficient cells. We found that MeCP2 protein levels increase significantly during neural differentiation and accumulate at constitutive heterochromatin. Statistical analysis of Mecp2 wild type neurons revealed a significant clustering of heterochromatin per nuclei with progressing differentiation. In contrast we found Mecp2 deficient neurons and astroglia cells to be significantly impaired in heterochromatin reorganization. Our results (i) introduce a new and manageable cellular model to study the molecular effects of Mecp2 deficiency, and (ii) support the view of MeCP2 as a central protein in heterochromatin architecture in maturating cells, possibly involved in stabilizing their differentiated state.

Original languageEnglish
Article numbere47848
JournalPLoS One
Volume7
Issue number10
DOIs
Publication statusPublished - Oct 24 2012

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Bertulat, B., de Bonis, M. L., Della Ragione, F., Lehmkuhl, A., Milden, M., Storm, C., Jost, K. L., Scala, S., Hendrich, B., D'Esposito, M., & Cardoso, M. C. (2012). MeCP2 Dependent Heterochromatin Reorganization during Neural Differentiation of a Novel Mecp2-Deficient Embryonic Stem Cell Reporter Line. PLoS One, 7(10), [e47848]. https://doi.org/10.1371/journal.pone.0047848