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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


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.

Original languageEnglish
Article number107795
JournalCell Reports
Issue number12
StatePublished - 23 Jun 2020


  • differential expression
  • differential targeting
  • gender
  • gene regulation
  • gene regulatory networks
  • GTEx
  • sex differences
  • sexual dimorphism


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