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Cell Metab. 2016 May 10;23(5):909-20. doi: 10.1016/j.cmet.2016.04.002. Epub 2016 Apr 28.

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

Author information

1
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
4
Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA.
5
INSERM U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
6
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
7
Institute of Cellular Therapeutics, Allegheny Health Network, 320 East North Avenue, Pittsburgh, PA 15212, USA.
8
Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA.
9
Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
10
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine (Oncology Division), Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: seungkim@stanford.edu.

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.

PMID:
27133132
PMCID:
PMC4864151
DOI:
10.1016/j.cmet.2016.04.002
[Indexed for MEDLINE]
Free PMC Article

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