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MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function
- Source :
- Diabetes
- Publication Year :
- 2015
- Publisher :
- American Diabetes Association, 2015.
-
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.
- Subjects :
- Maf Transcription Factors, Large
Methyltransferase
Endocrinology, Diabetes and Metabolism
MafB Transcription Factor
Nuclear Receptor Coactivators
030209 endocrinology & metabolism
Biology
Cell Line
Mice
03 medical and health sciences
Transactivation
0302 clinical medicine
Insulin-Secreting Cells
Maf Transcription Factors
Internal Medicine
Animals
Humans
Glucose homeostasis
RNA, Small Interfering
Transcription factor
030304 developmental biology
0303 health sciences
Histone-Lysine N-Methyltransferase
Molecular biology
DNA-Binding Proteins
Islet Studies
MAFB
NCOA6
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 64
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....b3c0e92b81831ed6baa8629de544fe74