Sex Differences in Gene Expression and Regulatory Networks across 29 Human Tissues

Camila M Lopes-Ramos; Cho-Yi Chen; Marieke L Kuijjer; Joseph N Paulson; Abhijeet R Sonawane; Maud Fagny; John Platig; Kimberly Glass; John Quackenbush; Dawn L DeMeo

doi:10.1016/j.celrep.2020.107795

Sex Differences in Gene Expression and Regulatory Networks across 29 Human Tissues

Cell Rep. 2020 Jun 23;31(12):107795. doi: 10.1016/j.celrep.2020.107795.

Authors

Affiliations

¹ Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
² Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.
³ Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
⁴ Department of Biostatistics, Product Development, Genentech Inc., San Francisco, CA, USA.
⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Genetique Quantitative et Evolution-Le Moulon, Universite Paris-Saclay, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Centre National de la Recherche Scientifique, AgroParisTech, Gif-sur-Yvette, France.
⁷ Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁸ Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: johnq@hsph.harvard.edu.
⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: dawn.demeo@channing.harvard.edu.

Abstract

Sex differences manifest in many diseases and may drive sex-specific therapeutic responses. To understand the molecular basis of sex differences, we evaluated sex-biased gene regulation by constructing sample-specific gene regulatory networks in 29 human healthy tissues using 8,279 whole-genome expression profiles from the Genotype-Tissue Expression (GTEx) project. We find sex-biased regulatory network structures in each tissue. Even though most transcription factors (TFs) are not differentially expressed between males and females, many have sex-biased regulatory targeting patterns. In each tissue, genes that are differentially targeted by TFs between the sexes are enriched for tissue-related functions and diseases. In brain tissue, for example, genes associated with Parkinson's disease and Alzheimer's disease are targeted by different sets of TFs in each sex. Our systems-based analysis identifies a repertoire of TFs that play important roles in sex-specific architecture of gene regulatory networks, and it underlines sex-specific regulatory processes in both health and disease.

Keywords: GTEx; differential expression; differential targeting; gender; gene regulation; gene regulatory networks; sex differences; sexual dimorphism.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Chromosomes, Human, X / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Female
Gene Expression Regulation*
Gene Regulatory Networks*
Humans
Male
Organ Specificity / genetics*
Sex Characteristics*
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

DNA-Binding Proteins
Transcription Factors
c-MYC-associated zinc finger protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding