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Detailed Functional Characterization of a Waist-Hip Ratio Locus in 7p15.2 Defines an Enhancer Controlling Adipocyte Differentiation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. German Canc Res Ctr, Heidelberg, Germany.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2019 (English)In: ISCIENCE, ISSN 2589-0042, Vol. 20, p. 42-59Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 20, p. 42-59
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Cell and Molecular Biology
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URN: urn:nbn:se:uu:diva-397133DOI: 10.1016/j.isci.2019.09.006ISI: 000493388000004PubMedID: 31557715OAI: oai:DiVA.org:uu-397133DiVA, id: diva2:1374013
Funder
Swedish Research Council, 2015-02907Knut and Alice Wallenberg Foundation, 2013.0126NIH (National Institute of Health), R01DK106236EXODIAB - Excellence of Diabetes Research in SwedenAvailable from: 2019-11-28 Created: 2019-11-28 Last updated: 2019-11-28Bibliographically approved

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Castillejo-Lopez, CasimiroHetty, SusanneWadelius, ClaesIngelsson, Erik
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Medicinsk genetik och genomikScience for Life Laboratory, SciLifeLabDepartment of Medical SciencesClinical diabetology and metabolismMolecular epidemiology
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