@article{e51fe878d7074eaca77cdb92b2a1a207,
title = "Age-dependent pancreatic gene regulation reveals mechanisms governing human β cell function",
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.",
author = "Arda, {H. Efsun} and Lingyu Li and Jennifer Tsai and Torre, {Eduardo A.} and Yenny Rosli and Heshan Peiris and Spitale, {Robert C.} and Chunhua Dai and Xueying Gu and Kun Qu and Pei Wang and Jing Wang and Markus Grompe and Raphael Scharfmann and Snyder, {Michael S.} and Rita Bottino and Powers, {Alvin C.} and Chang, {Howard Y.} and Kim, {Seung K.}",
note = "Funding Information: We gratefully acknowledge organ donors and their families for tissue procurement. We thank R. Banerjee, W. Goodyer, S. Kundu, and H. Chen for advice or help with tissue procurement; G. Oliver (St. Jude Children{\textquoteright}s Research Hospital) for advice on SIX3 antibody; D. Cohen (Harvard Medical School), D. Blodgett, and D. Harlan (UMass Medical School) for protocols and help with intracellular sorting; C. Dorrell (Oregon Health Sciences University) for FACS advice; and K. Lee for assistance with confocal microscopy in the Stanford Cell Sciences Imaging Facility (supported by NIH grant 1S10OD01058001A1). We thank P. Batista, D. Simsek-Buck, and members of S.K.K.{\textquoteright}s lab for comments on the manuscript. H.E.A. was supported by a postdoctoral fellowship from the JDRF and a training grant to the Endocrinology Division, Department of Medicine, Stanford (5T32DK007217-39, NIDDK). R.C.S. was supported by the A.P. Giannini Foundation. M.S.S. is a cofounder and member of the scientific advisory board of Personalis. He is a member of the scientific advisory board (SAB) of Axiomx, Genapsys, and SensOmics. H.Y.C. is a founder of Epinomics and served on the SAB of RaNA Therapeutics. Joint work in H.Y.C.{\textquoteright}s, M.S.S.{\textquoteright}s, R.P.{\textquoteright}s, A.C.P.{\textquoteright}s, and S.K.K.{\textquoteright}s groups was supported by the NIH Beta Cell Biology Consortium (UO1DK089532 to S.K.K.). Work in A.C.P.{\textquoteright}s group was also supported by grants from the NIH (DK72473, DK89572, DK104211), the JDRF, the Department of Veterans Affairs, and the Vanderbilt Diabetes Research and Training Center (DK20593), and in S.K.K.{\textquoteright}s group by the Howard Hughes Medical Institute, Helmsley Charitable Trust, the H.L. Snyder Foundation, the Elser Foundation, the Doolittle Trust, and the JDRF. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = may,
day = "10",
doi = "10.1016/j.cmet.2016.04.002",
language = "English (US)",
volume = "23",
pages = "909--920",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "5",
}