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.
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: H Efsun
authors.initials: HE
authors.lastname: Arda
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Lingyu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tsai
authors.affiliation: Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Torre
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yenny
authors.initials: Y
authors.lastname: Rosli
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Heshan
authors.initials: H
authors.lastname: Peiris
authors.affiliation: Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Spitale
authors.affiliation: Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Dai
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Xueying
authors.initials: X
authors.lastname: Gu
authors.affiliation: Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Qu
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
authors.affiliation: INSERM U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Scharfmann
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Snyder
authors.affiliation: Institute of Cellular Therapeutics, Allegheny Health Network, 320 East North Avenue, Pittsburgh, PA 15212, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Bottino
authors.affiliation: 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.
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
authors.affiliation: 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.
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Seung K
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics*; D002454:Cell Differentiation; D002469:Cell Separation; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003920:Diabetes Mellitus / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D042421:Histone Code; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008875:Middle Aged; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D055815:Young Adult
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; D014157:Transcription Factors