Bmi-1 regulates the Ink4a/Arf locus to control pancreatic β-cell proliferation
Open accessAbstract
The molecular mechanisms that regulate the age-induced increase of p16 INK4a expression associated with decreased β-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 β-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 β-cell proliferation during aging and regeneration.
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The age-related decline in β-cell expansion correlates with epigenetic changes at the Cdkn2a locus, which encodes p16Ink4a and p19Arf.
“This decline correlates with epigenetic changes at the Cdkn2a locus, which encodes the cell cycle inhibitors, p16Ink4a and p19Arf [30,31].”
From Expansion of β-cell mass in response to pregnancy (2010) · cites this paper as [30]
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BackgroundIncreasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
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- Authors
- Dhawan, S., Tschen, S.-I., & Bhushan, A.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2009-04-15
- Volume
- 23
- Issue
- 8
- Pages
- 906-911
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2675870
- OpenAlex
- W2116165602
- Cited by
- 210
- References
- 9
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 8 · 2021: 13 · 2020: 9 · 2019: 10 · 2018: 7 · 2017: 10 · 2016: 16 · 2015: 14 · 2014: 14 · 2013: 21 · 2012: 17
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Larry L. Hillblom Foundation
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK068763, DK-80996, DK068763, R01DK080996)
- 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 › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- BMI1, INK4a/ARF locus, p16INK4a, pancreatic beta-cell proliferation, beta cell regeneration, histone modifications, MLL1, H3K4 trimethylation, Polycomb group proteins, histone code
- MeSH terms
- Aging, Animals, Cell Line, Female, Gene Expression Regulation, Male, Mice, Inbred C57BL, Nuclear Proteins, Protein Binding, Proto-Oncogene Proteins, Repressor Proteins, Glucose Intolerance, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p16, Gene Expression Profiling, Cell Proliferation, Insulin-Secreting Cells, Mice, Polycomb Repressive Complex 1
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