title: A Whole-Genome RNA Interference Screen Reveals a Role forSpry2in Insulin Transcription and the Unfolded Protein Response.
abstract: Insulin production by the pancreatic β-cell is required for normal glucose homeostasis. While key transcription factors that bind to the insulin promoter are known, relatively little is known about the upstream regulators of insulin transcription. Using a whole-genome RNA interference screen, we uncovered 26 novel regulators of insulin transcription that regulate diverse processes including oxidative phosphorylation, vesicle traffic, and the unfolded protein response (UPR). We focused onSpry2-a gene implicated in human type 2 diabetes by genome-wide association studies but without a clear connection to glucose homeostasis. We showed thatSpry2is a novel UPR target and its upregulation is dependent on PERK. Knockdown ofSpry2resulted in reduced expression of Serca2, reduced endoplasmic reticulum calcium levels, and induction of the UPR.Spry2deletion in the adult mouse β-cell caused hyperglycemia and hypoinsulinemia. Our study greatly expands the compendium of insulin promoter regulators and demonstrates a novel β-cell link betweenSpry2and human diabetes.
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Pappalardo
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Deeksha
authors.initials: D
authors.lastname: Gambhir Chopra
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA.|Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hennings
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Hunter
authors.initials: H
authors.lastname: Richards
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Justin
authors.initials: J
authors.lastname: Choe
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Yang
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Luc
authors.initials: L
authors.lastname: Baeyens
authors.affiliation: Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Kenny
authors.initials: K
authors.lastname: Ang
authors.affiliation: Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Steven
authors.initials: S
authors.lastname: Chen
authors.affiliation: Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Arkin
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA.|Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, San Francisco, CA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: German
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA.|Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: McManus
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA gregory.ku@ucsf.edu.|Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, San Francisco, CA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Ku
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D017346:Protein Serine-Threonine Kinases; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D017304:Annexin A5; D002118:Calcium; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019892:eIF-2 Kinase; C485561:SPRY2 protein, human; C118389:Spry2 protein, mouse