title: The Transcription Factor Nfatc2 Regulates β-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets.
abstract: Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the expression of ~40% of the T2D-associated genes is linked to a broad region on mouse chromosome (Chr) 2. As all but 9 of these genes are not physically located on Chr 2, linkage to Chr 2 suggests a genomic factor(s) located on Chr 2 regulates their expression in trans. The transcription factor Nfatc2 is physically located on Chr 2 and its expression demonstrates cis linkage; i.e., its expression maps to itself. When conditioned on the expression of Nfatc2, linkage for the T2D-associated genes was greatly diminished, supporting Nfatc2 as a driver of their expression. Plasma insulin also showed linkage to the same broad region on Chr 2. Overexpression of a constitutively active (ca) form of Nfatc2 induced β-cell proliferation in mouse and human islets, and transcriptionally regulated more than half of the T2D-associated genes. Overexpression of either ca-Nfatc2 or ca-Nfatc1 in mouse islets enhanced insulin secretion, whereas only ca-Nfatc2 was able to promote β-cell proliferation, suggesting distinct molecular pathways mediating insulin secretion vs. β-cell proliferation are regulated by NFAT. Our results suggest that many of the T2D-associated genes are downstream transcriptional targets of NFAT, and may act coordinately in a pathway through which NFAT regulates β-cell proliferation in both mouse and human islets.
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Mark P
authors.identifier: http://orcid.org/0000-0002-7405-5552
authors.initials: MP
authors.lastname: Keller
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Pradyut K
authors.identifier: http://orcid.org/0000-0002-9922-4877
authors.initials: PK
authors.lastname: Paul
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Rabaglia
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Donnie S
authors.identifier: http://orcid.org/0000-0002-7108-3718
authors.initials: DS
authors.lastname: Stapleton
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Schueler
authors.affiliation: Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Aimee Teo
authors.identifier: http://orcid.org/0000-0003-3783-2807
authors.initials: AT
authors.lastname: Broman
authors.affiliation: Department of Statistics, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Shuyun Isabella
authors.initials: SI
authors.lastname: Ye
authors.affiliation: Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Leng
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Christopher J
authors.identifier: http://orcid.org/0000-0001-6077-4081
authors.initials: CJ
authors.lastname: Brandon
authors.affiliation: Sage Bionetworks, Seattle, Washington.
authors.forename: Elias Chaibub
authors.initials: EC
authors.lastname: Neto
authors.affiliation: Institute for Systems Biology, Seattle, Washington.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Plaisier
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Shane P
authors.identifier: http://orcid.org/0000-0002-9359-7808
authors.initials: SP
authors.lastname: Simonett
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Melkam A
authors.initials: MA
authors.lastname: Kebede
authors.affiliation: Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Gloria M
authors.identifier: http://orcid.org/0000-0002-4223-9947
authors.initials: GM
authors.lastname: Sheynkman
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Klein
authors.affiliation: Institute for Systems Biology, Seattle, Washington.
authors.forename: Nitin S
authors.initials: NS
authors.lastname: Baliga
authors.affiliation: Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Lloyd M
authors.identifier: http://orcid.org/0000-0002-6652-8639
authors.initials: LM
authors.lastname: Smith
authors.affiliation: Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Karl W
authors.identifier: http://orcid.org/0000-0002-4914-6671
authors.initials: KW
authors.lastname: Broman
authors.affiliation: Department of Statistics, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Brian S
authors.identifier: http://orcid.org/0000-0002-8774-9377
authors.initials: BS
authors.lastname: Yandell
authors.affiliation: Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Kendziorski
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D016678:Genome; D055106:Genome-Wide Association Study; D006801:Humans; D007328:Insulin / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008820:Mice, Obese; D050778:NFATC Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D007328:Insulin; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C494007:Nfatc2 protein, mouse