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PMID: 19390085 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Bmi-1 regulates the Ink4a/Arf locus to control pancreatic beta-cell proliferation.

Genes & development ·Vol. 23 ·No. 8 ·2009-04-15 ·Pages 906-11

Dhawan S, Tschen SI, Bhushan A

Abstract

The molecular mechanisms that regulate the age-induced increase of p16(INK4a) expression associated with decreased beta-cell proliferation and regeneration are not well understood. We report that in aged islets, derepression of the Ink4a/Arf locus is associated with decreased Bmi-1 binding, loss of H2A ubiquitylation, increased MLL1 recruitment, and a concomitant increase in H3K4 trimethylation. During beta-cell regeneration these histone modifications are reversed resulting in reduced p16(INK4a) expression and increased proliferation. We suggest that PcG and TrxG proteins impart a combinatorial code of histone modifications on the Ink4a/Arf locus to control beta-cell proliferation during aging and regeneration.

MeSH Terms
Aging Animals Cell Line Cell Proliferation Cyclin-Dependent Kinase Inhibitor p16/metabolism Female Gene Expression Profiling Gene Expression Regulation Glucose Intolerance/metabolism Insulin-Secreting Cells/cytology Male Mice Mice, Inbred C57BL Mice, Knockout Nuclear Proteins/metabolism Polycomb Repressive Complex 1 Protein Binding Proto-Oncogene Proteins/metabolism Repressor Proteins/metabolism
Chemicals
Bmi1 protein, mouse Cyclin-Dependent Kinase Inhibitor p16 Nuclear Proteins Proto-Oncogene Proteins Repressor Proteins Polycomb Repressive Complex 1
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Dhawan Sangeeta
Larry L. Hillblom Islet Research Center, Department of Medicine, University of California at Los Angeles, Los Angeles, California 90024, USA.
Tschen Shuen-Ing
Bhushan Anil
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
1549-5477
DOI
10.1101/gad.1742609
Published
2009-04-15
Pages
906-11
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2675870
Subset
IM
Grants
NIDDK NIH HHS · R01 DK068763 · United States
NIDDK NIH HHS · R01 DK080996 · United States
NIDDK NIH HHS · DK-068763 · United States
NIDDK NIH HHS · DK-80996 · United States
External Links
PubMed source DOI: 10.1101/gad.1742609 PMC Full Text View journal details
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