Transcriptome Analysis of the Human Tibial Nerve Identifies Sexually Dimorphic Expression of Genes Involved in Pain, Inflammation, and Neuro-Immunity

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.

Sexual Dimorphism of Early Transcriptional Reprogramming in Dorsal Root Ganglia After Peripheral Nerve Injury

“…Recent transcriptomics data in animals identified sex-specific PNI responses in DRG ( North et al, 2019 ; Ray et al, 2019 ; Stephens et al, 2019 ; Chernov et al, 2020 ; Mecklenburg et al, 2020 ; Paige et al, 2020 ; Tavares-Ferreira et al, 2020 ; Yu et al, 2020 ). However, sex differences in the immediate post-injury early-response transcriptional events remain not well understood.…”

“…Inflammatory, neuropathic, and idiopathic hypersensitivity and persistent pain conditions often have greater prevalence and symptom severity in women as compared to men ( Unruh, 1996 ; Greenspan et al, 2007 ; Fillingim et al, 2009 ; Mogil, 2012 ; Sorge and Totsch, 2017 ; Boerner et al, 2018 ). Transcriptome RNA-sequencing (RNA-seq)-based analyses of human DRG at baseline ( Ray et al, 2019 ) and in patients with radicular/neuropathic pain ( North et al, 2019 ) highlighted DRG’s central role in sex-specific gene regulation. Likewise, emerging research has revealed sexual dimorphism in rodent DRG transcriptomes in response to peripheral nerve injury ( Stephens et al, 2019 ; Ahlström et al, 2021 ), hyperalgesic priming by interleukin 6 (Il-6; Paige et al, 2020 ), sciatic nerve injection of myelin basic protein (MBP) derived peptides ( Chernov et al, 2020 ), and other stimuli.…”

“…Likewise, emerging research has revealed sexual dimorphism in rodent DRG transcriptomes in response to peripheral nerve injury ( Stephens et al, 2019 ; Ahlström et al, 2021 ), hyperalgesic priming by interleukin 6 (Il-6; Paige et al, 2020 ), sciatic nerve injection of myelin basic protein (MBP) derived peptides ( Chernov et al, 2020 ), and other stimuli. Transcriptome differences in DRG have been implicated in female-prevalent hypersensitivity partly due to the activity of prostaglandin signaling and neuroendocrine mechanisms involving prolactin receptors ( North et al, 2019 ; Ray et al, 2019 ; Chernov et al, 2020 ; Mecklenburg et al, 2020 ; Paige et al, 2020 ; Tavares-Ferreira et al, 2020 ).…”

Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits

“…A threshold of > = 0.75 or < = -0.75 was chosen for the SSMD to identify stably expressed genes that were systematically changing between conditions (Supplementary File 1, Sheet 1). Fold changes were calculated (with a smoothing factor of 0.5 added to both the numerator and denominator 86 for every gene with stable expression in at least one condition for each comparison (Supplementary File 1, Sheet 1).…”

Transcriptomic sex differences in sensory neuronal populations of mice

“…These points suggest that sex differences in gene expression could be detected in nociceptive pathways of mice and humans. For instance, sex differences in expression of genes involved in pain and inflammation, such as Ntrk1 , Ccl2 , Pdgfr , Traf3 and Vegfa were observed in human tibial nerve 16 . Neuropathic pain conditions are also associated with sex-dependent differential expression of inflammatory genes and transcription factors in human DRG tissues 17 .…”