title: MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function.
abstract: Insulin produced by islet β-cells plays a critical role in glucose homeostasis, with type 1 and type 2 diabetes both resulting from inactivation and/or loss of this cell population. Islet-enriched transcription factors regulate β-cell formation and function, yet little is known about the molecules recruited to mediate control. An unbiased in-cell biochemical and mass spectrometry strategy was used to isolate MafA transcription factor-binding proteins. Among the many coregulators identified were all of the subunits of the mixed-lineage leukemia 3 (Mll3) and 4 (Mll4) complexes, with histone 3 lysine 4 methyltransferases strongly associated with gene activation. MafA was bound to the ∼1.5 MDa Mll3 and Mll4 complexes in size-fractionated β-cell extracts. Likewise, closely related human MAFB, which is important to β-cell formation and coproduced with MAFA in adult human islet β-cells, bound MLL3 and MLL4 complexes. Knockdown of NCOA6, a core subunit of these methyltransferases, reduced expression of a subset of MAFA and MAFB target genes in mouse and human β-cell lines. In contrast, a broader effect on MafA/MafB gene activation was observed in mice lacking NCoA6 in islet β-cells. We propose that MLL3 and MLL4 are broadly required for controlling MAFA and MAFB transactivation during development and postnatally.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: David W
authors.initials: DW
authors.lastname: Scoville
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Cyphert
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
authors.forename: Lan
authors.initials: L
authors.lastname: Liao
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Al
authors.initials: A
authors.lastname: Reynolds
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Shuangli
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN roland.stein@vanderbilt.edu.
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000378:metabolism*; D051258:MafB Transcription Factor / Q000378:metabolism*; D051379:Mice; D056918:Nuclear Receptor Coactivators / Q000378:metabolism; D034741:RNA, Small Interfering
chemical_list: D004268:DNA-Binding Proteins; C452979:KMT2C protein, human; C485159:MAFA protein, human; D051473:Maf Transcription Factors, Large; D051258:MafB Transcription Factor; C486559:NCOA6 protein, human; D056918:Nuclear Receptor Coactivators; D034741:RNA, Small Interfering; D011495:Histone-Lysine N-Methyltransferase; C530816:MLL4 protein, human