Sex differences in human adipose tissue gene expression and genetic regulation involve adipogenesis
- Warren D. Anderson1,
- Joon Yuhl Soh1,
- Sarah E. Innis2,
- Alexis Dimanche3,
- Lijiang Ma4,
- Carl D. Langefeld5,
- Mary E. Comeau5,
- Swapan K. Das6,
- Eric E. Schadt4,
- Johan L.M. Björkegren4 and
- Mete Civelek1,2
- 1Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA;
- 2Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22904, USA;
- 3Physics Department, Southwestern University, Georgetown, Texas 78626, USA;
- 4Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 5Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101, USA;
- 6Department of Internal Medicine, Section of Endocrinology and Metabolism, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101, USA
Abstract
Sex differences in adipose tissue distribution and function are associated with sex differences in cardiometabolic disease. While many studies have revealed sex differences in adipocyte cell signaling and physiology, there is a relative dearth of information regarding sex differences in transcript abundance and regulation. We investigated sex differences in subcutaneous adipose tissue transcriptional regulation using omic-scale data from ∼3000 geographically and ethnically diverse human samples. We identified 162 genes with robust sex differences in expression. Differentially expressed genes were implicated in oxidative phosphorylation and adipogenesis. We further determined that sex differences in gene expression levels could be related to sex differences in the genetics of gene expression regulation. Our analyses revealed sex-specific genetic associations, and this finding was replicated in a study of 98 inbred mouse strains. The genes under genetic regulation in human and mouse were enriched for oxidative phosphorylation and adipogenesis. Enrichment analysis showed that the associated genetic loci resided within binding motifs for adipogenic transcription factors (e.g., PPARG and EGR1). We demonstrated that sex differences in gene expression could be influenced by sex differences in genetic regulation for six genes (e.g., FADS1 and MAP1B). These genes exhibited dynamic expression patterns during adipogenesis and robust expression in mature human adipocytes. Our results support a role for adipogenesis-related genes in subcutaneous adipose tissue sex differences in the genetic and environmental regulation of gene expression.
Footnotes
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.264614.120.
- Received April 10, 2020.
- Accepted August 27, 2020.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
