Talk 16
Presenter: Alan Attie
Thursday, 11:40am

Genetic Identification of Nfatc2 as a Critical Regulator of Pancreatic Islet Function

Alan Attie1, Brian Yandell2,7, Elias Chaibub Neto4, Christopher Plaiser5, Mary Rabaglia1, Donnie Stapleton1, Karl Broman3, Christina Kendziorski3, Aimee Teo Broman3, Nitin Baliga4, Angie Oler1, Kathy Schueler1, Sushant Bhatnagar1, Matt Bruss1, Eric Schadt6 and Mark Keller1
Departments of Biochemistry1, Statistics2, Horticulture7 and Biostatistics & Medical Informatics3, University of Wisconsin, Madison, WI. 4Department of Computational Biology, Sage Bionetworks, Seattle, WA. 5Institute for Systems Biology, Seattle, WA. 6Department of Genetics and Genomics Sciences, Mt. Sinai School of Medicine, New York, NY

We mapped numerous diabetes-related traits in an F2 inter-cross between obese (Lepob/ob) C57BL/6 (diabetes resistant) and obese BTBR (diabetes susceptible) mice. We obtained a strong linkage for plasma insulin to a locus on chromosome 2. We also mapped eQTL traits for 6 tissues (pancreatic islets, liver, adipose tissue, skeletal muscle, kidney and hypothalamus). In islets, the expression of ~600 transcripts mapped in trans to the same region on chromosome 2 as plasma insulin. These transcripts included 36 genes previously identified in human GWAS as having an association for T2D. We asked if the islet genes mapping to the chromosome 2 locus were enriched for a motif in their promoter that is consistent with any known transcription factor. The promoter region of 85 genes were enriched for a motif recognized by Nfatc2 (p<10-5), which is physically located at the locus. Finally, a formal test for causality (QTLChr2 → Genecis → Genetrans) identified Nfatc2 as the strongest candidate regulator of the trans-mapping expression traits at the chromosome 2 locus. The overexpression of a constitutively active form of Nfatc2 in mouse islets significantly augmented insulin secretion in response to several insulin secretagogues. In summary, four lines of evidence converged on Nfatc2 as a critical regulator of beta-cell function.