Biology subjects

Stephens, K. E.

Publications and source records attributed to Stephens, K. E..

6 recordsLinked to original sources

bioRxiv2026

Degraded myelin is associated with cold hypersensitivity in paclitaxel-induced peripheral neuropathy

Cold allodynia is a debilitating symptom of chemotherapy-induced peripheral neuropathy (CIPN), a side effect of many chemotherapeutics, including paclitaxel (PTX). CIPN is highly prevalent and can lead to cessation of chemotherapy, threatening cancer patient survival. PTX induces cold-evoked pain in 60% of CIPN patients and this pain is a predictor for more severe neuropathy. Cold is transduced by primary sensory neurons in dorsal root ganglia (DRG). PTX can induce maladaptive changes in gene expression that lead to dysregulated nociceptor function. Previous work examining PTX-induced transcriptional changes have been unable to isolate mechanisms associated with pathological cold pain. The epigenetic changes that underlie long-lasting transcriptional changes in PTX-induced persistent cold hypersensitivity are not known. Following three consecutive cycles of PTX, we find that mice continue to exhibit cold hypersensitivity for a minimum of four weeks following the resolution of PTX-induced mechanical hypersensitivity. This exclusive cold hypersensitivity phenotype allows us to examine the mechanisms that specifically underlie pathological cold pain. During this period of PTX-induced cold hypersensitivity, we found decreased expression of genes whose expression is necessary for myelin sheath formation and maintenance, degraded myelin sheaths in the distal sciatic nerve, and decreased chromatin accessibility at genomic regions that contain binding motifs for pro-myelinating transcription factors. Our findings suggest that epigenetic-regulated myelin programs perpetuate myelin degradation and drive pathological cold pain. Our improved understanding of the specific mechanisms that maintain myelin degradation during cold hypersensitivity will improve cold pain management, facilitate the completion of cancer treatment, and improve the quality of life for chronic pain patients.

neuroscience↗

bioRxiv2025

A novel model of paclitaxel-induced peripheral neuropathy produces a clinically relevant phenotype in mice

One of the most common adverse side effects of chemotherapeutics is chemotherapy-induced peripheral neuropathy (CIPN). Paclitaxel, a highly effective chemotherapeutic, is associated with a high incidence of paclitaxel-induced peripheral neuropathy (PIPN) that persists for over a year in 64% of patients and worsens with cumulative PTX dose. Patients experiencing PIPN may reduce the dosage of chemotherapy or halt treatment due to this pain. Current preclinical models have improved our understanding of PIPN but have been ineffective in generating translational therapeutic options. These models administer a single cycle of PTX to induce a PIPN phenotype of mechanical and cold hypersensitivity that resolves within 28 days. However, this does not mirror the clinical dosing regimen or the patient experience of CIPN. In this study, we conduct a comprehensive and longitudinal behavioral profile of our novel model of PIPN in mice where three consecutive cycles of PTX (4 mg/kg, 4 doses/cycle) are given to mimic the clinical administration. Repeated cycles of PTX caused long-lasting mechanical and cold hypersensitivity in male and female C57Bl/6J mice that mirrors clinical observations of persistent CIPN without causing detrimental effects to rodent overall health, normal rodent behavior, or motor function. Our findings support the use of this translational model to facilitate a better understanding of PIPN and the development of effective treatment options. Improved pain management will enable the completion of cancer treatment, decrease health care expenditure, decrease mortality, and improve the quality of life for cancer patients and survivors.

neuroscience↗

bioRxiv2022

Identification of regulatory elements in primary sensory neurons involved in neuropathic pain

Chronic pain is a significant public health issue that is often refractory to existing therapies. Here we use a multiomic approach to identify cis-regulatory elements that show differential chromatin accessibility, and reveal transcription factor (TF) binding motifs with functional regulation in the dorsal root ganglion (DRG), which contain cell bodies of primary sensory neurons, after nerve injury. We integrated RNA-seq to understand how differential chromatin accessibility after nerve injury may influence gene expression. Using TF protein arrays and chromatin immunoprecipitation-qPCR, we confirmed C/EBP{gamma} binding to a differentially accessible sequence and used RNA-seq to identify processes in which C/EBP{gamma} plays an important role. Our findings offer insights into TF motifs that are associated with chronic pain. These data show how interactions between chromatin landscapes and TF expression patterns may work together to determine gene expression programs in DRG neurons after nerve injury.

neuroscience↗

bioRxiv2021

Dynamics of global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain

Efforts to understand genetic variability involved in an individuals susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms. To examine the transcriptomic and epigenetic basis of chronic pain that resides in the peripheral nervous system, we used RNA-seq and ATAC-seq of the rat dorsal root ganglion (DRG) to identify novel molecular pathways associated with pain hypersensitivity in two well-studied persistent pain models induced by Chronic Constriction Injury (CCI) of the sciatic nerve and intra-plantar injection of Complete Freunds Adjuvant (CFA) in rats. Our RNA-seq studies identify a variety of biological process related to synapse organization, membrane potential, transmembrane transport, and ion binding. Interestingly, genes that encode transcriptional regulators were disproportionately downregulated in both models. Our ATAC-seq data provide a comprehensive map of chromatin accessibility changes in the DRG. A total of 1123 regions showed changes in chromatin accessibility in one or both models when compared to the naive and 31 shared differentially accessible regions (DAR)s. Functional annotation of the DARs identified disparate molecular functions enriched for each pain model which suggests that chromatin structure may be altered differently following sciatic nerve injury and hind paw inflammation. Motif analysis identified 17 DNA sequences known to bind transcription factors in the CCI DARs and 33 in the CFA DARs. Two motifs were significantly enriched in both models. Our improved understanding of the changes in chromatin accessibility that occur in chronic pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG. SummaryShared transcriptomic and epigenetic changes in two animal models improves our understanding of how chromatin structural changes alter DRG gene expression under persistent pain conditions.

neuroscience↗

bioRxiv2021

Human brain region-specific variably methylated regions (VMRs) are enriched for heritability of distinct neuropsychiatric traits

BACKGROUNDDNA methylation dynamics in the brain are associated with normal development and neuropsychiatric disease and differ across functionally distinct brain regions. Previous studies of genome-wide methylation differences among human brain regions focused on limited numbers of individuals and one to two brain regions. RESULTSUsing GTEx samples, we have generated a resource of DNA methylation in purified neuronal nuclei from 8 brain regions as well as lung and thyroid tissues from 12-23 donors. We identified differentially methylated regions between brain regions (DMRs) among neuronal nuclei in both CpG (181,146) and non-CpG (264,868) contexts, few of which were unique to a single pair-wise comparison. This significantly expands the knowledge of differential methylation across the brain by 10-fold. In addition, we present the first differential methylation analysis among neuronal nuclei from basal ganglia tissues and identified 2,295 unique CpG DMRs, many associated with ion transport. Consistent with prior studies, CpG DMRs were enriched in regulatory regions while non-CpG DMRs were enriched in intergenic regions. We also identified 81,130 regions of variably CpG methylated regions (VMRs), i.e. variable methylation among individuals in the same brain region, which were enriched in regulatory regions and in CpG DMRs. Many VMRs were unique to a specific brain region, with only 202 common across all brain regions, as well as lung and thyroid. VMRs identified in the amygdala, anterior cingulate cortex, and hippocampus were enriched for heritability of schizophrenia. CONCLUSIONSThese data suggest that epigenetic variation in these particular human brain regions could be associated with the risk for this neuropsychiatric disorder.

genomics↗

bioRxiv2017

Sex differences in gene regulation in the dorsal root ganglion after nerve injury

Pain is a subjective experience derived from complex interactions among biological, environmental, and psychosocial pathways. Sex differences in pain sensitivity and chronic pain prevalence are well established. However, the molecular causes underlying these sex dimorphisms are poorly understood particularly with regard to the role of the peripheral nervous system. Here we sought to identify shared and distinct gene networks functioning in the peripheral nervous systems that may contribute to sex differences of pain after nerve injury. We performed RNA-seq on dorsal root ganglia following chronic constriction injury of the sciatic nerve in male and female rats. Analysis from paired naive and injured tissues showed that 1456 genes were differentially expressed between sexes. Appreciating sex-related gene expression differences and similarities in neuropathic pain models may help to improve the translational relevance to clinical populations and efficacy of clinical trials of this major health issue.

neuroscience↗