👤 Shanmathi Parameswaran

Innate lymphoid cells (ILCs) are rare, tissue-resident innate lymphocytes that functionally mirror CD4+ T helper cell lineages but lack antigen receptors. Type 3 ILCs (ILC3s) are enriched in the gut, airways, and mucosal lymphoid tissues, where they regulate inflammation and promote barrier integrity. To define the regulatory architecture of primary human ILC3s, we map promoter-anchored chromosomal contacts using high-resolution, low-input Promoter Capture Hi-C (PCHi-C) in these cells alongside CD4+ T cells. By combining statistical detection with a PCHi-C-adapted Activity-by-Contact approach, we link promoters to distal regulatory elements, identifying hundreds of ILC3-specific contacts. We use these maps to connect genome-wide association study (GWAS) risk variants for Crohn's disease to target genes using multiCOGS, a Bayesian framework that integrates PCHi-C with summary-statistic imputation and multivariate fine-mapping. This analysis highlights both known and unanticipated candidates, including Show less

Historically, 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) was thought to be the key enzyme responsible for testicular testosterone production. In humans, loss-of-function mutations in HSD17B3 impair testosterone production during prenatal life leading to impaired development of androgen-dependent tissues in 46,XY individuals. However, male mice with HSD17B3 deficiency exhibit normal testicular testosterone concentrations, normal development of reproductive organs and are fertile, suggesting that mice express other hydroxysteroid dehydrogenase enzymes capable of testicular testosterone synthesis. This study aimed to investigate whether 17β-hydroxysteroid dehydrogenase type 12 (HSD17B12), which can convert androstenedione to testosterone in mice but not in humans, compensates for the lack of HSD17B3 in Hsd17b3 knockout (KO) mice. We used CRISPR/Cas9 to substitute the amino acid in mouse HSD17B12 that is responsible for its ability to convert androstenedione to testosterone with the amino acid of the human enzyme that prevents androstenedione being used as a substrate. When this Hsd17b12 mutation was introduced into Hsd17b3 KO mice, males exhibited normal reproductive tracts but reduced testicular testosterone production with a consequential reduction in seminal vesicle weight. This suggests HSD17B12 contributes toward testosterone production in the absence of HSD17B3, but other enzymes must also contribute. We therefore quantified other testicular hydroxysteroid dehydrogenases, finding that HSD17B7 mRNA and protein was markedly upregulated in Hsd17b3 KO testes. We confirmed that mouse, but not human, HSD17B7 can produce testosterone in vitro. We conclude that compared to humans, mice exhibit increased plasticity in testosterone production via hydroxysteroid dehydrogenase enzymes to support androgen action and male fertility. Show less

Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced metastatic disease and exhibit a poor response to therapy, resulting in poor outcomes. The tumor microenvironment cytokine Oncostatin-M (OSM) initiates PDAC plasticity, inducing the reprogramming to a stem-like/mesenchymal state, which enhances metastasis and therapy resistance. Using a panel of PDAC cells driven through epithelial-mesenchymal transition (EMT) by OSM or the transcription factors ZEB1 or SNAI1, we find that OSM uniquely induces tumor initiation and gemcitabine resistance independently of its ability to induce a CD44HI/mesenchymal phenotype. In contrast, while ZEB1 and SNAI1 induce a CD44HI/mesenchymal phenotype and migration comparable with OSM, they are unable to promote tumor initiation or robust gemcitabine resistance. Transcriptomic analysis identified that OSM-mediated stemness requires MAPK activation and sustained, feed-forward transcription of OSMR. MEK and ERK inhibitors prevented OSM-driven transcription of select target genes and stem-like/mesenchymal reprogramming, resulting in reduced tumor growth and resensitization to gemcitabine. We propose that the unique properties of OSMR, which hyperactivates MAPK signaling when compared with other IL6 family receptors, make it an attractive therapeutic target, and that disrupting the OSM-OSMR-MAPK feed-forward loop may be a novel way to therapeutically target the stem-like behaviors common to aggressive PDAC. Small-molecule MAPK inhibitors may effectively target the OSM/OSMR-axis that leads to EMT and tumor initiating properties that promote aggressive PDAC. Show less