title: MBD2 regulates TH17 differentiation and experimental autoimmune encephalomyelitis by controlling the homeostasis of T-bet/Hlx axis.
abstract: Unlike genetic alterations, epigenetic modifications are reversible and amenable to pharmacological interventions, which make them appealing targets for clinical therapy. However, little is known about epigenetic regulation in experimental autoimmune encephalomyelitis (EAE). Here we demonstrated that methyl-CpG-binding domain protein 2 (MBD2), an epigenetic regulator, controls autoimmunity and EAE through T-bet/Hlx. Tbx21 and Hlx underwent a DNA methylation turnover upon polarizations and a unique methylation pattern was essential for TH17 development. Loss of Mbd2 resulted in a defect for reading the information encoded by this methylation turnover, which disrupted the homeostasis of T-bet/Hlx axis and suppressed TH17 differentiation. DNA demethylation induced similar effect on helper T cell differentiation. Therefore, Mbd2(-/-) mice were completely protected from EAE. Pathogenic splenocytes isolated from wild-type mice challenged with MOG35-55 could adoptively transfer disease to Mbd2(-/-) mice. In addition, Mbd2(-/-) mice reconstituted with unstimulated wild-type splenocytes developed EAE as wild-type mice did. These data would provide novel insights into epigenetic regulation of EAE.
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
authors.forename: Jixin
authors.initials: J
authors.lastname: Zhong
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Yu
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: The Center for Biotechnology and Genomic Medicine, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Rao
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
authors.forename: Long
authors.initials: L
authors.lastname: He
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Tu
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
authors.forename: Qiaohong
authors.initials: Q
authors.lastname: Lai
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The Center for Biotechnology and Genomic Medicine, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Kuczma
authors.affiliation: The Center for Biotechnology and Genomic Medicine, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Piatr
authors.initials: P
authors.lastname: Kraj
authors.affiliation: Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical College, Dongguan 523808, China.
authors.forename: Jun-Fa
authors.initials: JF
authors.lastname: Xu
authors.affiliation: Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Feili
authors.initials: F
authors.lastname: Gong
authors.affiliation: Department of Hematology, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.affiliation: Laboratory of Experimental Medicine, Universite Libre de Bruxelles, Route de Lennik 808, CP 618, B-1070 Brussels, Belgium.
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Neurology, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China. Electronic address: wwang@tjh.tjmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China. Electronic address: wangcy@tjh.tjmu.edu.cn.
authors.forename: Cong-Yi
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D044127:Epigenesis, Genetic / Q000235:genetics / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; C489999:Hlx protein, mouse; D018398:Homeodomain Proteins; C489326:Mbd2 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; C445081:myelin oligodendrocyte glycoprotein (35-55)
keywords: EAE; Epigenetic; MBD2; Methylation; T(H)17; T-bet