First Author | Scoville DW | Year | 2015 |
Journal | Diabetes | Volume | 64 |
Issue | 11 | Pages | 3772-83 |
PubMed ID | 26180087 | Mgi Jnum | J:247098 |
Mgi Id | MGI:5924678 | Doi | 10.2337/db15-0281 |
Citation | Scoville DW, et al. (2015) MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet beta-Cell Function. Diabetes 64(11):3772-83 |
abstractText | Insulin produced by islet beta-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 beta-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 approximately 1.5 MDa Mll3 and Mll4 complexes in size-fractionated beta-cell extracts. Likewise, closely related human MAFB, which is important to beta-cell formation and coproduced with MAFA in adult human islet beta-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 beta-cell lines. In contrast, a broader effect on MafA/MafB gene activation was observed in mice lacking NCoA6 in islet beta-cells. We propose that MLL3 and MLL4 are broadly required for controlling MAFA and MAFB transactivation during development and postnatally. |