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Tissue Network Analysis Points to Significant Sex-Related Regulatory Differences

NEW YORK – Sex-specific gene regulatory features appear to turn up extensively in human tissues, according to a new systems biology-based analysis. 

For a paper appearing in Cell Reports on Tuesday, researchers from the US, Taiwan, Norway, and France put together gene regulatory networks representing 29 tissue types in nearly 500 healthy Genotype-Tissue Expression (GTEx) project participants. From the resulting set of almost 8,300 networks, they documented apparent sex-related differences in transcription factor targeting and activity despite relatively subtle sex-related expression differences within most tissues considered.

"Our results provide a repertoire of sex-biased regulatory processes and their regulatory drivers," wrote researchers led by co-corresponding authors Dawn DeMeo and John Quackenbush, researchers affiliated with Brigham and Women's Hospital and Harvard. They further noted that these findings "underline the importance of considering systems-level differences in gene regulation to understand sex differences contributing to health and disease."

The team suggested that the new collection of gene regulatory networks may help to interpret findings from future studies of biology and disease through a sex- and tissue-specific lens, moving investigators closer to the goal of designing clinical and research studies with participant sex, and its effects, in mind.

"Sex differences have been recognized among the most significantly understudied aspects of human disease," the authors wrote. "Historically, sex has not been properly taken into account, many experimental studies have been done only on males, the sex chromosomes have been excluded from analyses, and sequence mapping protocols have not account[ed] for sex chromosome biases."

Along with analyses on tissue-specific and sex-specific gene expression in the 29 tissue types done with a tool called voom, the researchers combined RNA sequencing profiles for 8,279 samples — contributed by 360 male and 188 female GTEx participants — with available data on transcription factor binding motifs, protein-protein interactions, and other available clues to put together individual gene regulatory networks for each sample with modeling approaches known as PANDA and LIONESS.

While differential gene expression between sexes was relatively modest on the non-sex chromosomes, generally occurring in tissues and pathways already known for sex-specific expression, the team reported, gene regulatory differences in male and female participants were widespread, stemming in part from varied transcription factor targets.

"We found that gene regulatory processes vary by sex across tissues and that many [transcription factors] have sex-biased targeting patterns," the authors wrote, noting that "genes that are differentially targeted between males and females are enriched for disease and tissue-related functions." 

Moreover, they called the current results "a significant step forward on understanding how sex differences manifest in gene regulatory networks and underscore the importance of looking beyond gene expression."