Identification &functional characterization of SIM1 obesity-associated variants Obesity leads to an increased risk for type 2 diabetes, heart attack, many types of cancer, hypertension, stroke, and is estimated to soon be the leading cause of death in the US. Through twin and family studies, obesity has been found to have a 40-70% heritability rate, pointing to a strong genetic etiology. In a large-scale human resequencing project of obese and lean individuals we have discovered that rare coding variants in the Single Minded 1 (SIM1) gene could have a large effect on obesity predisposition. Haploinsuficiency of SIM1 in humans and in heterozygous null Sim1 mice was shown to lead to severe obesity, and a common non- synonymous haplotype predisposes to obesity, suggesting that both altered function and altered expression of SIM1 can lead to obesity susceptibility. In this proposal, we will take advantage of comparative genomics coupled with zebrafish and mouse enhancer assays to identify SIM1 regulatory elements. Using this approach we have already uncovered five hypothalamus enhancers in the SIM1 region. These functional regulatory elements in addition to the SIM1 coding region will be sequenced in several large cohorts of obese and lean individuals in order to uncover obesity-associated variants. Obesity-associated coding variants will be assessed for their effect on the protein function using an in vitro functional assay that we generated for this project. Enhancer variants will be assayed for differential enhancer activity in mice compared to the reference allele. Future assays, such as removal of an obesity-associated enhancer in mice and further sequencing of SIM1 obesity-associated variants in the NIDDK Longitudinal Assessment of Bariatric Surgery (LABS) cohort (a cohort of adults that have undergone bariatric surgery and that is being analyzed for their subsequent outcome) will be considered as a follow-up to this proposal. Identifying and functionally characterizing SIM1 obesity-associated nucleotide variants will increase our understanding of the different genetic contributions of SIM1 to this phenotype. In addition, this study will serve as a model to functionally characterize the effect of noncoding regulatory elements on human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK090382-03
Application #
8640171
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Karp, Robert W
Project Start
2012-05-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$336,038
Indirect Cost
$118,538
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Eckalbar, Walter L; Schlebusch, Stephen A; Mason, Mandy K et al. (2016) Transcriptomic and epigenomic characterization of the developing bat wing. Nat Genet 48:528-36
Ahituv, Nadav (2016) Exonic enhancers: proceed with caution in exome and genome sequencing studies. Genome Med 8:14
Booker, Betty M; Friedrich, Tara; Mason, Mandy K et al. (2016) Bat Accelerated Regions Identify a Bat Forelimb Specific Enhancer in the HoxD Locus. PLoS Genet 12:e1005738
Yang, Song; Oksenberg, Nir; Takayama, Sachiko et al. (2015) Functionally conserved enhancers with divergent sequences in distant vertebrates. BMC Genomics 16:882
Jorgenson, Eric; Makki, Nadja; Shen, Ling et al. (2015) A genome-wide association study identifies four novel susceptibility loci underlying inguinal hernia. Nat Commun 6:10130
Hesse, Robert G; Kouklis, Gayle K; Ahituv, Nadav et al. (2015) The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration. Elife 4:
Luizon, Marcelo R; Ahituv, Nadav (2015) Uncovering drug-responsive regulatory elements. Pharmacogenomics 16:1829-41
Matharu, Navneet; Ahituv, Nadav (2015) Minor Loops in Major Folds: Enhancer-Promoter Looping, Chromatin Restructuring, and Their Association with Transcriptional Regulation and Disease. PLoS Genet 11:e1005640
Oksenberg, N; Haliburton, G D E; Eckalbar, W L et al. (2014) Genome-wide distribution of Auts2 binding localizes with active neurodevelopmental genes. Transl Psychiatry 4:e431
Evans, Daniel S; Calton, Melissa A; Kim, Mee J et al. (2014) Genetic association study of adiposity and melanocortin-4 receptor (MC4R) common variants: replication and functional characterization of non-coding regions. PLoS One 9:e96805

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