Cargando…
MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function
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 r...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613979/ https://www.ncbi.nlm.nih.gov/pubmed/26180087 http://dx.doi.org/10.2337/db15-0281 |
_version_ | 1782396345123864576 |
---|---|
author | Scoville, David W. Cyphert, Holly A. Liao, Lan Xu, Jianming Reynolds, Al Guo, Shuangli Stein, Roland |
author_facet | Scoville, David W. Cyphert, Holly A. Liao, Lan Xu, Jianming Reynolds, Al Guo, Shuangli Stein, Roland |
author_sort | Scoville, David W. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4613979 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-46139792016-11-01 MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function Scoville, David W. Cyphert, Holly A. Liao, Lan Xu, Jianming Reynolds, Al Guo, Shuangli Stein, Roland Diabetes Islet Studies 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. American Diabetes Association 2015-11 2015-07-15 /pmc/articles/PMC4613979/ /pubmed/26180087 http://dx.doi.org/10.2337/db15-0281 Text en © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. |
spellingShingle | Islet Studies Scoville, David W. Cyphert, Holly A. Liao, Lan Xu, Jianming Reynolds, Al Guo, Shuangli Stein, Roland MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function |
title | MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function |
title_full | MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function |
title_fullStr | MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function |
title_full_unstemmed | MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function |
title_short | MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function |
title_sort | mll3 and mll4 methyltransferases bind to the mafa and mafb transcription factors to regulate islet β-cell function |
topic | Islet Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613979/ https://www.ncbi.nlm.nih.gov/pubmed/26180087 http://dx.doi.org/10.2337/db15-0281 |
work_keys_str_mv | AT scovilledavidw mll3andmll4methyltransferasesbindtothemafaandmafbtranscriptionfactorstoregulateisletbcellfunction AT cypherthollya mll3andmll4methyltransferasesbindtothemafaandmafbtranscriptionfactorstoregulateisletbcellfunction AT liaolan mll3andmll4methyltransferasesbindtothemafaandmafbtranscriptionfactorstoregulateisletbcellfunction AT xujianming mll3andmll4methyltransferasesbindtothemafaandmafbtranscriptionfactorstoregulateisletbcellfunction AT reynoldsal mll3andmll4methyltransferasesbindtothemafaandmafbtranscriptionfactorstoregulateisletbcellfunction AT guoshuangli mll3andmll4methyltransferasesbindtothemafaandmafbtranscriptionfactorstoregulateisletbcellfunction AT steinroland mll3andmll4methyltransferasesbindtothemafaandmafbtranscriptionfactorstoregulateisletbcellfunction |