Abstract
Sex differences in gene expression are important contributors to normal physiology and mechanisms of disease. This is increasingly apparent in understanding and potentially treating chronic pain where molecular mechanisms driving sex differences in neuronal plasticity are giving new insight into why certain chronic pain disorders preferentially affect women vs. men. Large transcriptomic resources are now available and can be used to mine for sex differences to gather insight from molecular profiles using donor cohorts. We performed in-depth analysis of 248 human tibial nerve (hTN) transcriptomes from the GTEx Consortium project to gain insight into sex-dependent gene expression in the peripheral nervous system (PNS). We discover 149 genes with sex differential gene expression. Many of the more abundant genes in men are associated with inflammation and appear to be primarily expressed by glia or immune cells, with some genes downstream of Notch signaling. In women, we find the differentially expressed transcription factor SP4 that is known to drive a regulatory program, and may impact sex differences in PNS physiology. Many of these 149 differentially expressed (DE) genes have some previous association with chronic pain but few of them have been explored thoroughly. Additionally, using clinical data in the GTEx database, we identify a subset of DE, sexually dimorphic genes in diseases associated with chronic pain: arthritis and Type II diabetes. Our work creates a unique resource that identifies sexually dimorphic gene expression in the human PNS with implications for discovery of sex-specific pain mechanisms.
Highlights
Sex-differential gene regulation and resultant changes in transcriptome, proteome, and metabolome shape sexually dimorphic physiology and behavior in animals
We identified an additional 74 genes in males (Figure 2; Table 2), and 27 genes in females that were differentially expressed (DE) at the 75th percentile (Figure 3; Table 2). While several of these genes have been previously identified in the literature (Chen et al, 2016; Gershoni and Pietrokovski, 2017), our analysis identified new DE genes not identified in previous studies (Chen et al, 2016; Gershoni and Pietrokovski, 2017) including several that are potentially relevant to peripheral nervous system (PNS) function and pain mechanisms, including ISLR2, SP4, and TPPP2 (Chu et al, 2011; Aoki et al, 2014; Panza et al, 2015)
To identify neural tissue enriched genes, we identified genes in our DE gene list with high (≥0.5) Neural Proportion Scores suggesting that they are primarily expressed in neurons or glia
Summary
Sex-differential gene regulation and resultant changes in transcriptome, proteome, and metabolome shape sexually dimorphic physiology and behavior in animals. Sex-differential molecular profiles in human tissues have a profound effect on health, resulting in disease susceptibility, prevalence and pathophysiology differences between sexes. Sex-Differential Human Tibial Nerve Transcriptome have a staggering global disease burden, and prevalence of many chronic pain conditions like fibromyalgia and neuralgia have been shown to be higher in women (De Toledo et al, 2016), and sex-differential molecular changes in the peripheral and central nervous system (CNS) have been implicated in preclinical models (Mogil, 2012). Human tibial nerve (hTN) transcriptomes, which contains axons from DRG neurons, along with a panel of other harvested tissues, have been profiled using RNA-sequencing (RNA-seq) in hundreds of male and female donors as part of the GTEx project (Lonsdale et al, 2013). Some studies have characterized sex-differential gene expression changes (Chen et al, 2016; Gershoni and Pietrokovski, 2017) and investigated the evolutionary and regulatory basis of such changes across the repertoire of GTEx tissues, but none have focused on the hTN
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