title: Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function.
abstract: Autism spectrum disorders such as Rett syndrome (RTT) have been hypothesized to arise from defects in experience-dependent synapse maturation. RTT is caused by mutations in MECP2, a nuclear protein that becomes phosphorylated at S421 in response to neuronal activation. We show here that disruption of MeCP2 S421 phosphorylation in vivo results in defects in synapse development and behavior, implicating activity-dependent regulation of MeCP2 in brain development and RTT. We investigated the mechanism by which S421 phosphorylation regulates MeCP2 function and show by chromatin immunoprecipitation-sequencing that this modification occurs on MeCP2 bound across the genome. The phosphorylation of MeCP2 S421 appears not to regulate the expression of specific genes; rather, MeCP2 functions as a histone-like factor whose phosphorylation may facilitate a genome-wide response of chromatin to neuronal activity during nervous system development. We propose that RTT results in part from a loss of this experience-dependent chromatin remodeling.
authors: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Sonia
authors: S
authors: Cohen
authors: Harrison W
authors: HW
authors: Gabel
authors: Martin
authors: M
authors: Hemberg
authors: Ashley N
authors: AN
authors: Hutchinson
authors: L Amanda
authors: LA
authors: Sadacca
authors: Daniel H
authors: DH
authors: Ebert
authors: David A
authors: DA
authors: Harmin
authors: Rachel S
authors: RS
authors: Greenberg
authors: Vanessa K
authors: VK
authors: Verdine
authors: Zhaolan
authors: Z
authors: Zhou
authors: William C
authors: WC
authors: Wetsel
authors: Anne E
authors: AE
authors: West
authors: Michael E
authors: ME
authors: Greenberg
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000378:metabolism / Q000502:physiology; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation / Q000379:methods; D003712:Dendrites / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D055879:Gene Knock-In Techniques / Q000379:methods; D016678:Genome / Q000502:physiology*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation
chemical_list: D002843:Chromatin; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2