title: The histone methyltransferase MMSET regulates class switch recombination.
abstract: Wolf-Hirschhorn syndrome (WHS) is a genetic disease with characteristic facial features and developmental disorders. Of interest, loss of the MMSET gene (also known as WHSC1) is considered to be responsible for the core phenotypes of this disease. Patients with WHS also display Ab deficiency, although the underlying cause of this deficiency is unclear. Recent studies suggest that the histone methyltransferase activity of MMSET plays an important role in the DNA damage response by facilitating the recruitment of 53BP1 to sites of DNA damage. We hypothesize that MMSET also regulates class switch recombination (CSR) through its effect on 53BP1. In this study, we show that MMSET indeed plays an important role in CSR through its histone methyltransferase activity. Knocking down MMSET expression impaired 53BP1 recruitment as well as the germline transcription of the Igh switch regions, resulting in defective CSR but no effect on cell growth and viability. These results suggest that defective CSR caused by MMSET deficiency could be a cause of Ab deficiency in WHS patients.
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Huadong
authors.initials: H
authors.lastname: Pei
authors.forename: Xiaosheng
authors.initials: X
authors.lastname: Wu
authors.forename: Tongzheng
authors.initials: T
authors.lastname: Liu
authors.forename: Kefei
authors.initials: K
authors.lastname: Yu
authors.forename: Diane F
authors.initials: DF
authors.lastname: Jelinek
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D002460:Cell Line; D005786:Gene Expression Regulation; D056426:Genetic Loci; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008745:Methylation; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D000071857:Tumor Suppressor p53-Binding Protein 1; D060152:V(D)J Recombination / Q000235:genetics*; D054877:Wolf-Hirschhorn Syndrome / Q000235:genetics
chemical_list: D006657:Histones; D007143:Immunoglobulin Heavy Chains; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human