title: MeCP2 reinforces STAT3 signaling and the generation of effector CD4+ T cells by promoting miR-124-mediated suppression of SOCS5.
abstract: Methyl CpG binding protein 2 (MeCP2) is an X-linked, multifunctional epigenetic regulator that is best known for its role in the neurological disorder Rett syndrome; however, it is also linked to multiple autoimmune disorders. We examined a potential role for MeCP2 in regulating the responses of CD4+ T cells to stimulation with antigen. MeCP2 was indispensable for the differentiation of naïve CD4+ T cells into T helper type 1 (T(H)1) and T(H)17 cells and for T(H)1- or T(H)17-mediated pathologies in vitro and in vivo. Loss of MeCP2 in CD4+ T cells impaired the expression of the microRNA (miR) miR-124 and consequently relieved miR-124-mediated repression of the translation of suppressor of cytokine signaling 5 (Socs5) mRNA. The resulting accumulation of SOCS5 inhibited the cytokine-dependent activation of signal transducer and activator of transcription 1 (STAT1) and STAT3, which are necessary for the differentiation of T(H)1 and T(H)17 cells, respectively. Upon silencing of MeCP2, primary neurons and astrocytes also failed to respond properly to STAT3-dependent signaling stimulated by neurotrophic factors. Together, these findings suggest that the regulation of STAT3 signaling may represent a common etiology underpinning the roles of MeCP2 in both the nervous and immune systems.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Chaoran
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: McRae
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Lykken
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Sevilla
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Si-Qi
authors.initials: SQ
authors.lastname: Liu
authors.affiliation: Center for Quantitative Biomedicine, Third Military Medical University, Chongqing 400038, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
mesh_terms: D000818:Animals; D052160:Benzothiazoles; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism; D019175:DNA Methylation; D003959:Diamines; D005786:Gene Expression Regulation / Q000276:immunology*; D006652:Histological Techniques; D008156:Luciferases; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009930:Organic Chemicals; D016133:Polymerase Chain Reaction; D011804:Quinolines; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D016207:Cytokines; D003959:Diamines; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D009930:Organic Chemicals; D011804:Quinolines; D050796:STAT3 Transcription Factor; C485811:Socs5 protein, mouse; C494087:Stat3 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; C098022:SYBR Green I; D008156:Luciferases