title: Regulation of mRNA splicing by MeCP2 via epigenetic modifications in the brain.
abstract: Mutations of X-linked gene Methyl CpG binding protein 2 (MECP2) are the major causes of Rett syndrome (RTT), a severe neurodevelopmental disorder. Duplications of MECP2-containing genomic segments lead to severe autistic symptoms in human. MECP2-coding protein methyl-CpG-binding protein 2 (MeCP2) is involved in transcription regulation, microRNA processing and mRNA splicing. However, molecular mechanisms underlying the involvement of MeCP2 in mRNA splicing in neurons remain largely elusive. In this work we found that the majority of MeCP2-associated proteins are involved in mRNA splicing using mass spectrometry analysis with multiple samples from Mecp2-null rat brain, mouse primary neuron and human cell lines. We further showed that Mecp2 knockdown in cultured cortical neurons led to widespread alternations of mRNA alternative splicing. Analysis of ChIP-seq datasets indicated that MeCP2-regulated exons display specific epigenetic signatures, with DNA modification 5-hydroxymethylcytosine (5hmC) and histone modification H3K4me3 are enriched in down-regulated exons, while the H3K36me3 signature is enriched in exons up-regulated in Mecp2-knockdown neurons comparing to un-affected neurons. Functional analysis reveals that genes containing MeCP2-regulated exons are mainly involved in synaptic functions and mRNA splicing. These results suggested that MeCP2 regulated mRNA splicing through interacting with 5hmC and epigenetic changes in histone markers, and provide functional insights of MeCP2-mediated mRNA splicing in the nervous system.
authors.affiliation: Institute of Neuroscience, Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai, 200031, China.
authors.forename: Tian-Lin
authors.initials: TL
authors.lastname: Cheng
authors.affiliation: Department of Biostatistics and Computational Biology, School of Life Science, Fudan University, Shanghai, 200436, China.
authors.forename: Jingqi
authors.initials: J
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China.
authors.forename: Huida
authors.initials: H
authors.lastname: Wan
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Tang
authors.affiliation: Department of Biostatistics and Computational Biology, School of Life Science, Fudan University, Shanghai, 200436, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Tian
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China.
authors.forename: Lujian
authors.initials: L
authors.lastname: Liao
authors.affiliation: Institute of Neuroscience, Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai, 200031, China.
authors.forename: Zilong
authors.initials: Z
authors.lastname: Qiu
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D042421:Histone Code; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism; D051381:Rats
chemical_list: D051783:Methyl-CpG-Binding Protein 2; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine