Cited by 222Pancreatic function and diabetesDiabetes and associated disordersGenomics and Chromatin Dynamics

Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function

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Arda, H. Efsun, Li, Lingyu, Tsai, Jennifer, Torre, Eduardo A., Rosli, Yenny, Peiris, Heshan, Spitale, Robert C., Dai, Chunhua +11 more·2016·Cell Metabolism

Abstract

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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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.
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2016-05
Volume
23
Issue
5
Pages
909-920
ISSN
1550-4131 (ISSN-L)
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
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 › Surgery › 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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