人类骨骼肌中广泛的性别差异基因表达及调控

Extensive differential gene expression and regulation by sex in human skeletal muscle.

作者信息

Hanks Sarah C, Mauger Abigail S, Varshney Arushi, Ciotlos Dan L, Manickam Nandini, Narisu Narisu, Shumway Alexandria J, Orchard Peter, Erdos Michael R, Sweeney Michael D, Okamoto Jeffrey, Jackson Anne U, Stringham Heather M, Bonnycastle Lori L, Zhou Xiang, Lakka Timo A, Mohlke Karen L, Tuomilehto Jaakko, Laakso Markku, Boehnke Michael, Sethupathy Praveen, Collins Francis S, Koistinen Heikki A, Parker Stephen C J, Scott Laura J

机构信息

Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.

出版信息

Cell Genom. 2025 Aug 13;5(8):100915. doi: 10.1016/j.xgen.2025.100915. Epub 2025 Jun 5.

DOI:10.1016/j.xgen.2025.100915

PMID:40480217

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12366654/

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.

摘要

鉴定性别差异基因调控元件对于理解健康和疾病的性别差异模式至关重要。我们利用来自281份骨骼肌活检样本的批量和单核RNA测序（RNA-seq）以及单核ATAC-seq数据，在细胞类型和全组织水平上表征基因表达和调控中的性别差异。我们发现，在三种肌纤维类型和批量组织中，超过2100个基因存在高度一致的性别偏向性表达。与线粒体活性和能量代谢相关的基因通路富集了男性偏向性表达，而与信号转导和细胞分化相关的基因通路则富集了女性偏向性表达。我们发现广泛的性别偏向性染色质可及性富集于近端和远端基因调控状态；在基因启动子中，性别偏向性染色质可及性与性别偏向性表达呈正相关。长链非编码RNA（lncRNA）和微小RNA（miRNA）在纤维类型和批量数据中也分别表现出广泛的性别偏向性表达。总之，这些结果突出了骨骼肌中性别差异基因调控的核机制和细胞质机制。