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Cited by 64Pancreatic function and diabetesGenomics and Chromatin DynamicsDiabetes and associated disorders

MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function

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Scoville, David W., Cyphert, Holly A., Liao, Lan, Xu, Jianming, Reynolds, Al, Guo, Shuangli, Stein, Roland·2015·Diabetes
DOI 10.2337/db15-0281PMC PMC4613979
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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.

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  • Some studies show that signalling-dependent and cell type-specific TFs are capable of recruiting MLL4 to establish H3K4me1 at enhancers.

    “While some studies show that signalling-dependent and cell type-specific TFs are capable of recruiting MLL4 to establish H3K4me1 at enhancers44–47, whether HNF4A has this function is not known.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [46]

    The Discussion (page unavailable) reports that the islet β-cell transcription factors MAFA and MAFB recruit MLL3/4 complexes, supporting the recruitment part of the claim. It reports H3K4 trimethylation at a regulated gene, however, not establishment of H3K4me1 at enhancers; the Results describe enhancer monomethylation as a general capability of the methyltransferase family rather than a finding of this study. (LLM, conf=0.88)

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Cited by

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Authors
Scoville, D. W., Cyphert, H. A., Liao, L., Xu, J., Reynolds, A., Guo, S., & Stein, R.
Affiliations
  • Vanderbilt University (US)
  • Baylor College of Medicine (US)
Corresponding author
Stein, Roland
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2015-07-15
Volume
64
Issue
11
Pages
3772-3783
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db15-0281
PMC
PMC4613979
OpenAlex
W1824828567
Cited by
64
References
1
Citations by year
2026: 4 · 2025: 2 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 7 · 2020: 10 · 2019: 7 · 2018: 4 · 2017: 4 · 2016: 7 · 2015: 2
FWCI
5.71
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5p60dk020593-31)
  • National Eye Institute (EY08126, P30EY008126)
  • National Cancer Institute (R01CA112403, CA68485, CA 112403, R01CA193455, P30CA068485)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-090570, P60-DK020593, DK59637, F32-DK-102283-01, DK-58404, DK 20593, U24DK059637, DK-058242, F32DK102283, P01DK059820, R01DK058242, P30DK058404, P30DK020593, T32DK007061, R01DK090570)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD015052, HD 15052)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
MLL3, KMT2D, MafA, MAFB, pancreatic beta cells, transcriptional co-regulation, histone methylation, beta-cell function, gene activation
MeSH terms
Animals, Cell Line, DNA-Binding Proteins, Humans, Histone-Lysine N-Methyltransferase, RNA, Small Interfering, Insulin-Secreting Cells, MafB Transcription Factor, Mice, Maf Transcription Factors, Large, Nuclear Receptor Coactivators

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