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Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function
Open accessAbstract
Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however, establishing these age-dependent changes in humans has been challenging. Here, we describe a multimodal strategy for isolating pancreatic endocrine and exocrine cells from children and adults to identify age-dependent gene expression and chromatin changes on a genomic scale. These profiles revealed distinct proliferative and functional states of islet α cells or β cells and histone modifications underlying age-dependent gene expression changes. Expression of SIX2 and SIX3, transcription factors without prior known functions in the pancreas and linked to fasting hyperglycemia risk, increased with age specifically in human islet β cells. SIX2 and SIX3 were sufficient to enhance insulin content or secretion in immature β cells. Our work provides a unique resource to study human-specific regulators of islet cell maturation and function.
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“A DE study analyzing age-dependent gene regulation in human pancreas56 was used to get pancreas cell type specific priors.”
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Metadata
- Authors
- Arda, H. E., Li, L., Tsai, J., Torre, E. A., Rosli, Y., Peiris, H., Spitale, R. C., Dai, C., Gu, X., Qu, K., Wang, P., Wang, J., Grompe, M., Scharfmann, R., Snyder, M. S., Bottino, R., Powers, A. C., Chang, H. Y., & Kim, S. K.
- Affiliations
- Stanford Medicine (US)
- Vanderbilt University (US)
- Oregon Health & Science University (US)
- Allegheny Health Network (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kim, Seung K.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 23
- Issue
- 5
- Pages
- 909-920
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4864151
- OpenAlex
- W2343369957
- Cited by
- 222
- References
- 62
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 24 · 2023: 18 · 2022: 26 · 2021: 35 · 2020: 28 · 2019: 27 · 2018: 23 · 2017: 17 · 2016: 8
- FWCI
- 27.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000666)
- Agricultural Research Development Agency
- National Institutes of Health (5p60dk020593-31)
- National Institute of Diabetes and Digestive and Kidney Diseases (UC4DK104143, U01DK089532, P60-DK020593, U01DK089572, UC4DK104211, U01DK072473, T32DK007217, P30DK020593)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- pancreatic islet development, beta cell maturation, age-related gene expression, histone modifications, chromatin regulation, Six2, Six3, insulin secretion, islet cell proliferation, diabetes treatment, fasting hyperglycemia
- MeSH terms
- Adult, Aging, Cell Differentiation, Cell Separation, Child, Child, Preschool, Chromatin, Diabetes Mellitus, Humans, Infant, Middle Aged, Transcription Factors, Homeodomain Proteins, Gene Expression Regulation, Developmental, Histone Code, Chromatin Immunoprecipitation, Insulin-Secreting Cells, Young Adult, Transcriptome
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