Extensive differential gene expression and regulation by sex in human skeletal muscle
Sarah C. Hanks, Abigail S. Mauger, Arushi Varshney, Dan L. Ciotlos, Nandini Manickam, Narisu Narisu, Alexandria J. Shumway, Peter Orchard, Michael R. Erdos, M. D. Sweeney, Jeffrey Okamoto, Anne Jackson, Heather M. Stringham, Lori L. Bonnycastle, Xiang Zhou, Timo A. Lakka, Karen L. Mohlke, Jaakko Tuomilehto, Markku Laakso, Michael Boehnke, Praveen Sethupathy, Francis S. Collins, Heikki A. Koistinen, Stephen C.J. Parker, Laura J. Scott
Abstract
The identification of sex-differential gene regulatory elements is essential for understanding sex-differential patterns of health and disease. We leveraged bulk and single-nucleus RNA sequencing (RNA-seq) and single-nucleus ATAC-seq data from 281 skeletal muscle biopsies to characterize sex differences in gene expression and regulation at the cell-type and whole-tissue levels. We found highly concordant sex-biased expression of over 2,100 genes across the three muscle fiber types and bulk tissue. Gene pathways related to mitochondrial activity and energy metabolism were enriched for male-biased expression, whereas those related to signal transduction and cell differentiation were enriched for female-biased expression. We found widespread sex-biased chromatin accessibility enriched in proximal and distal gene regulatory states; in gene promoters, sex-biased chromatin accessibility was positively associated with sex-biased expression. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) also showed extensive sex-biased expression in the fiber-type and bulk data, respectively. Together, these results highlight nuclear and cytoplasmic mechanisms for sex-differential gene regulation in skeletal muscle.