biostudies-literatureCohen SNIDA NIH HHSNIMH NIH HHSNINDS NIH HHSNCI NIH HHSNIH HHSNIGMS NIH HHS72-85https://www.ebi.ac.uk/biostudies/studies/S-EPMC3226708biostudies-literatureUnknown72(1)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.NeuronGenome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function.PMC3226708R01 NS048276-08R00 NS058391R01 NS048276-06R01 NS048276-07R01 DA022202R01 NS048276-041R01NS048276K08MH90306R01 NS048276-05R01 NS048276-02R01 NS048276-03T32 GM007753R01 NS048276T32 CA009361R21 NS070250R01 NS048276-06S1DP2 OD006461K08 MH090306T32CA009361R01 NS048276-011R21NS070250-01A1K99 NS058391Sadacca LAHemberg MGabel HWCohen SGreenberg RSZhou ZWetsel WCEbert DHWest AEGreenberg MEHarmin DAHutchinson ANVerdine VKfalseGenome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function.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.2011-01-01T00:00:00Z2011 Oct2020-10-29T13:21:41Z2019-03-27T00:46:32ZS-EPMC32267082198237010.1016/j.neuron.2011.08.022