title: HIC1 epigenetically represses CIITA transcription in B lymphocytes.
abstract: Differentiation of B lymphocytes into isotope-specific plasma cells represents a hallmark event in adaptive immunity. During B cell maturation, expression of the class II transactivator (CIITA) gene is down-regulated although the underlying epigenetic mechanism is not completely defined. Here we report that hypermethylated in cancer 1 (HIC1) was up-regulated in differentiating B lymphocytes paralleling CIITA repression. Over-expression of HIC1 directly repressed endogenous CIITA transcription in B cells. Reporter assay and chromatin immunoprecipitation (ChIP) assay confirmed that HIC1 bound to the proximal CIITA type III promoter (-545/-113); mutation of a conserved HIC1 site within this region abrogated CIITA trans-repression. More important, depletion of HIC1 with small interfering RNA (siRNA) restored CIITA expression in differentiating B cells. Mechanistically, HIC1 preferentially interacted with and recruited DNMT1 and DNMT3b to the CIITA promoter to synergistically repress CIITA transcription. On the contrary, silencing of DNMT1/DNMT3b or inhibition of DNMT activity with 5-aza-dC attenuated CIITA trans-repression. Therefore, our data identify HIC1 as a novel factor involved in B cell differentiation acting as an epigenetic repressor of CIITA transcription.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China; Jiangsu Institute of Nuclear Medicine, Wuxi, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Bisheng
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China; Department of Gastroenterology, Second Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China; Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. Electronic address: kongxiaocen2010@163.com.
authors.forename: Xiaocen
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. Electronic address: yjxu@njmu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D000097584:DNA Methyltransferase 3B
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D015534:Trans-Activators; D000097584:DNA Methyltransferase 3B; C499808:HIC1 protein, human; C083728:MHC class II transactivator protein; C000619380:DNMT1 protein, human
keywords: CIITA; DNMT; Epigenetics; HIC1; Transcriptional regulation