Detailed Functional Characterization of a Waist-Hip Ratio Locus in 7p15.2 Defines an Enhancer Controlling Adipocyte Differentiation
Casimiro Castillejo-Lopez,
Milos Pjanic,
Anna Chiara Pirona,
Susanne Hetty,
Martin Wabitsch,
Claes Wadelius,
Thomas Quertermous,
Erik Arner,
Erik Ingelsson
Affiliations
Casimiro Castillejo-Lopez
Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Milos Pjanic
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
Anna Chiara Pirona
Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; German Cancer Research Center (DKFZ), Heidelberg, Germany
Susanne Hetty
Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Martin Wabitsch
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetes, University of Ulm, Ulm, Germany
Claes Wadelius
Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Thomas Quertermous
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA
Erik Arner
Laboratory for Applied Regulatory Genomics Network Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045 Japan
Erik Ingelsson
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA; Corresponding author
Summary: We combined CAGE sequencing in human adipocytes during differentiation with data from genome-wide association studies to identify an enhancer in the SNX10 locus on chromosome 7, presumably involved in body fat distribution. Using reporter assays and CRISPR-Cas9 gene editing in human cell lines, we characterized the role of the enhancer in adipogenesis. The enhancer was active during adipogenesis and responded strongly to insulin and isoprenaline. The allele associated with increased waist-hip ratio in human genetic studies was associated with higher enhancer activity. Mutations of the enhancer resulted in less adipocyte differentiation. RNA sequencing of cells with disrupted enhancer showed reduced expression of established adipocyte markers, such as ADIPOQ and LPL, and identified CHI3L1 on chromosome 1 as a potential gene involved in adipocyte differentiation. In conclusion, we identified and characterized an enhancer in the SNX10 locus and outlined its plausible mechanisms of action and downstream targets. : Genetics; Human Genetics; Specialized Functions of Cells; Transcriptomics Subject Areas: Genetics, Human Genetics, Specialized Functions of Cells, Transcriptomics
