Biology subjects

Sher, E.

Publications and source records attributed to Sher, E..

3 recordsLinked to original sources

bioRxiv2025

A pain-reducing Kv6.4 variant spares other Kv6 channels, offering a target for uterine pain

Uterine pain conditions such as dysmenorrhea and endometriosis are highly prevalent, poorly managed, and associated with long-term impacts on womens health. The identification of a rare KCNG4 variant (rs140124801; p.Val419Met) previously linked to reduced labor pain suggests Kv6.4 (encoded by KCNG4) may play a role in visceral nociception and offer a new target for non-opioid uterine pain relief. We analyzed UK Biobank data to evaluate clinical phenotypes associated with rare single nucleotide polymorphisms (SNPs) in the conserved TVGYG selectivity filter motif of the Kv6 family wherein p.Val419Met is located. Functional consequences of these variants were assessed using immunofluorescence in SHSY5Y cells to examine membrane trafficking, co-immunoprecipitation to investigate interactions between Kv6 subunits and Kv2.1, and single-cell RNA sequencing to determine expression patterns in mouse sensory neurons. Our genetic analysis identified 5,816 individuals heterozygous and 28 homozygous for the p.Val419Met variant, as well as 292 heterozygous carriers of the p.Thr418Met variant, all located in the Kv6.4 subunit. Neither variant was associated with increased risk for general, neurological, or pain-related disorders, even in homozygous p.Val419Met carriers, supporting a favorable safety profile. Kv6.4Val419Met has a dominant negative effect on wild type Kv6.4. However, this effect is specific to Kv6.4 as, in SHSY5Y cells, co-expression of Kv6.4Val419Met along with Kv6.1, Kv6.2 or Kv6.3, showed no effects on the efficient membrane localization of Kv6.1-3. In contrast, Kv6.4Thr418Met does not interfere with Kv6.4 trafficking or its heteromerization with Kv2.1. Additionally, In SHSY5Y cells, the equivalent p.Val419Met substitution, when introduced into Kv6.1, Kv6.2 and Kv6.3, disrupts their membrane localization, noting that these variants have never been reported. Co-immunoprecipitation shows that Kv6.4 does not interact with other Kv6 subunits and transcriptomic analysis shows that Kv6.4 is expressed in a distinct subset of mouse lumbar dorsal root ganglion neurons innervating pelvic organs. Our findings show that the Kv6.4Val419Met variant selectively disrupts Kv6.4 function without affecting other family members and is not linked to adverse phenotypes. This finding supports Kv6.4 as a highly selective and functionally distinct Kv6 subunit with no widespread deleterious effects on other Kv6 subunits, making it an attractive candidate for therapeutic targeting for uterine pain.

genetics↗

bioRxiv2025

Targeting DNA Polymerase Epsilon Leads to Tumor Clearance and Activation of an NF-κB mediated inflammatory response in Triple Negative Breast Cancer

Breast cancer remains the second leading cause of cancer-related mortality among women, with triple-negative breast cancer (TNBC) exhibiting a particularly poor five-year prognosis1. Here, we demonstrate that among genetic and pharmacological perturbations targeting DNA replication, suppression of DNA polymerase epsilon (POLE) in TNBC, induces a potent, TNBC-specific gene expression signature enriched in inflammatory cytokines that are transcriptional targets of NF-{kappa}B. TNBC cells exhibit markedly higher levels of DNA damage and canonical NF-{kappa}B activation compared to luminal breast cancer cells. Notably, NF-{kappa}B activation in this context depends on the canonical component RELA, but not the non-canonical component RELB. Mechanistically, ATM, STING, and RIG-I each contribute to NF-{kappa}B activation following POLE suppression. In vivo, POLE suppression in a murine TNBC model leads to cancer cell-intrinsic elimination of tumor burden and increased immune cell infiltration. Together, these findings support a model in which replication stress from POLE inhibition triggers robust NF-{kappa}B-mediated inflammation and immune microenvironment remodeling in TNBC and can independently trigger tumor eradication. These results suggest a potential therapeutic avenue for targeting POLE in TNBC.

cancer biology↗

bioRxiv2024

Investigation of cellular and molecular changes linked with neuropathic pain in healthy and injured human trigeminal nerves

Injuries to the trigeminal nerve, responsible for sensory innervation to the face, may occur during routine dental procedures, resulting in the formation of a neuroma accompanied by loss of sensation and/or symptoms of pain. In order to gain insight into the molecular mechanisms underpinning the sensory changes, single nuclei RNA sequencing and spatial transcriptomics were employed to profile the transcriptional landscape at single cell resolution of human trigeminal nerves and neuromas. Cellular and transcriptional changes were identified that correlated with the presence of pain, including an expansion of endothelial cells with a pro-inflammatory phenotype and over-expression of HLA-A, CXCL2 and CXCL8. Interactome analysis highlighted signalling changes linked with the presence of pain. HLA-A protein expression was confirmed in neuromas and positively correlated with symptoms of pain. The atlas generated represents a valuable resource for pain research, highlighting the role of inflammation, endothelial cell dysfunction and chemokine signalling in neuropathic pain.

neuroscience↗