👤 Bennett Davenport

Annotation of regulatory elements is essential for understanding mechanisms underlying gene regulation, particularly tissue-specific regulation in human and animals. Here, we characterize 274,682 enhancers and 25,975 promoters across 24 tissues from an adult female sheep using ChIP-seq, ATAC-seq, CAGE-seq, RRBS, WGBS, and RNA-seq. We identify seven neural development-related genes with over 10 enhancers in brain tissues, highlighting the role of tissue-specific regulation. Cis-regulatory enhancer-promoter combinations provide insights into tissue-specific enhancers, such as the cerebellum-specific enhancer (chr15: 57390520-57390685) regulating BDNF, which is expressed in both the cerebellum and cerebral cortex. Comparative analysis of enhancer-promoter combinations in human, mouse, pig, cattle, and sheep reveals ruminant-specific pathways, including pentose catabolism and long-chain fatty acid import regulation. A milk fat yield quantitative trait locus (QTL) identified within an enhancer interacts with the fat metabolism-related gene COMMD1, and a birth weight-associated QTL detected within a cerebellum-specific enhancer regulates XKR4. This study provides a robust framework for exploring cis-regulatory mechanisms and tissue-specific regulation, advancing the functional annotation of the sheep reference genome. Show less

Patients born with congenital porto-systemic shunts have been shown to have a high risk of benign and malignant liver tumors in otherwise healthy livers. This study aimed to evaluate the genetic landscape of liver tumors in patients with congenital porto-systemic shunts (CPSS) and correlate genotype with histological findings. Nodules from patients with CPSS and sporadic pediatric focal nodular hyperplasia (FNH) or FNH-like nodules were evaluated histologically and sequenced for a panel of 50 genes using next-generation sequencing. Thirty-eight nodules from 17 patients with CPSS were histologically classified as hepatoblastomas ( CPSS is strongly associated with nodules containing variants in Show less

Current guidelines recommend avoiding activities with the risk of contact during pregnancy, despite a lack of empirical data to support this recommendation. As a result, individuals who participate in contact and collision sports such as football or rugby are often confronted with difficult decisions and, in the absence of clear guidance, may resort to making choices based on personal experience, limited advice, or fear. We aimed to examine the impact of continued participation in contact sport during pregnancy on maternal and fetal health outcomes. We conducted an online survey study of individuals (≥ 18 years of age) who participated in contact or collision sports during pregnancy. The survey collected self-reported information on participant demographics, sport participation (type, hours, and contact exposure) from pre-conception to postpartum, maternal and infant health outcomes, feelings towards continuing/stopping participation in sport, and medical advice received during the perinatal period. Odds ratios or relative risk ratios with 95% confidence intervals were calculated for all categorical outcomes using regression adjusted for relevant covariates to compare outcomes in individuals who stopped participating in contact sport ≤ 12 weeks and > 12 weeks gestation as well as individuals who did and did not sustain a hit (contact) during pregnancy. Between September 2023 and February 2024, 395 participants (age 34.6 ± 5.0, months postpartum 27.2 ± 34.3; primarily from Australia, Canada, the UK, and the USA) were recruited to participate in the survey. Participants participated in contact sports for an average of 12.8 ± 6.4 weeks of pregnancy with 84 individuals sustaining hard hits and 114 individuals sustaining cumulative low impact contact. Participants reported partaking in a total of 11,687.2 h of contact exposure during pregnancy and the rate of adverse events was 1.11 per 1000 h of exposure. Overall, continued participation in contact sport during pregnancy was associated with better mental health status. Over half of participants stated that they had concerns about participating in contact sports during their pregnancy; however, 90% felt "happy" or "very happy" about continuing their sport during pregnancy. Pregnant individuals continue to participate in contact sports during pregnancy. Participants who continued participating in contact sports were more likely to report decreased depression. Continued participation in contact activities was not associated with the odds of other maternal or fetal complications during pregnancy or the postpartum period. Further investigation is required to direct safe participation in contact sports during pregnancy. Show less

The majority of pregnancy loss in ruminants occurs during the first two months of gestation, and a failure in placenta development is a major cause of pregnancy loss in cattle after day 20. Gaining a cell-type level understanding of normal placental development is essential for uncovering how this critical organ, responsible for nutrient exchange, gas transfer, and waste removal, fails during pregnancy loss. This study integrated single-cell RNA sequencing (scRNA-seq) from sheep and cattle during early placental development. Nineteen distinct cell populations were identified across species, with mesenchymal, epithelial, and trophoblast cells showing largely conserved expression profiles. Interestingly, two trophoblast clusters were unique to cattle, with one expressing IFNT2 (uninucleate) and another expressing CSH2 and PAG17 (binucleate). Genes associated with epithelial-to-mesenchymal transition (EMT), such as SNAI1, SNAI2, ZEB1, VIM, CDH1, and CLDN4, showed dynamic and prominent expression patterns in trophoblasts. Pseudotime and cell-cell signaling analyses supported the occurrence of EMT in uninucleate trophoblasts. Gene ontology comparisons revealed similarities between ruminant and human extravillous trophoblasts, suggesting conserved EMT across placental types. Collectively, these findings highlight EMT as a potentially critical process in early ruminant placentation. Show less

Regulatory T (Treg) cells are essential for the maintenance of immunological tolerance, yet the molecular components required for their maintenance and effector functions remain incompletely defined. Inactivation of VPS34 in Treg cells led to an early, lethal phenotype, with massive effector T cell activation and inflammation, like mice lacking Treg cells completely. However, VPS34-deficient Treg cells developed normally, populated the peripheral lymphoid organs and effectively supressed conventional T cells Show less

Patients with both major forms of diabetes would benefit from therapies that increase β-cell mass. Glucose, a natural mitogen, drives adaptive expansion of β-cell mass by promoting β-cell proliferation. We previously demonstrated that a carbohydrate response element-binding protein (ChREBPα) is required for glucose-stimulated β-cell proliferation and that overexpression of ChREBPα amplifies the proliferative effect of glucose. Here we found that ChREBPα reprogrammed anabolic metabolism to promote proliferation. ChREBPα increased mitochondrial biogenesis, oxygen consumption rates, and ATP production. Proliferation augmentation by ChREBPα required the presence of ChREBPβ. ChREBPα increased the expression and activity of Nrf2, initiating antioxidant and mitochondrial biogenic programs. The induction of Nrf2 was required for ChREBPα-mediated mitochondrial biogenesis and for glucose-stimulated and ChREBPα-augmented β-cell proliferation. Overexpression of Nrf2 was sufficient to drive human β-cell proliferation in vitro; this confirms the importance of this pathway. Our results reveal a novel pathway necessary for β-cell proliferation that may be exploited for therapeutic β-cell regeneration. Show less