Age-dependent pancreatic gene regulation reveals mechanisms governing human β cell function

H. Efsun Arda, Lingyu Li, Jennifer Tsai, Eduardo A. Torre, Yenny Rosli, Heshan Peiris, Robert C. Spitale, Chunhua Dai, Xueying Gu, Kun Qu, Pei Wang, Jing Wang, Markus Grompe, Raphael Scharfmann, Michael S. Snyder, Rita Bottino, Alvin C. Powers, Howard Y. Chang, Seung K. Kim

Research output: Contribution to journalArticle

70 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)909-920
Number of pages12
JournalCell Metabolism
Volume23
Issue number5
DOIs
StatePublished - May 10 2016

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ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

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. (2016). Age-dependent pancreatic gene regulation reveals mechanisms governing human β cell function. Cell Metabolism, 23(5), 909-920. https://doi.org/10.1016/j.cmet.2016.04.002