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Stuart C Sealfon

Publications and source records attributed to Stuart C Sealfon.

3 recordsLinked to original sources
PubMed2026

Regulation of murine follicle-stimulating hormone β subunit transcription by newly identified enhancers.

Activin-class ligands of the transforming growth factor β family induce follicle-stimulating hormone (FSH) production by pituitary gonadotrope cells in mice via the actions of the transcription factors SMAD3, SMAD4, and FOXL2, which bind to cis-elements in the FSHβ subunit (Fshb) promoter. An enhancer region for murine Fshb transcription was identified in vitro. However, deletion of the region using CRISPR-Cas9 did not affect FSH synthesis or secretion in mice. Using single-nucleus ATAC-seq of whole murine pituitaries, we identified 3 additional open chromatin regions upstream of Fshb exclusively in gonadotropes. These regions, as well as the Fshb gene, were fully or partially closed in gonadotropes of FSH-deficient mice with genetically or pharmacologically inactivated activin type II receptors. The initially characterized enhancer region did not significantly alter basal or activin-stimulated murine Fshb promoter-reporter activity in homologous LβT2 cells. In contrast, the other 3 open chromatin regions enhanced basal and activin A-stimulated Fshb promoter-reporter activity in LβT2 cells, with the 2 most distal showing the greatest effects. These 2 regions were open, exhibited enrichment of the enhancer mark H3K27ac, and were bound by SMAD2/3 and FOXL2 in response to activin A in LβT2 cells. The most distal enhancer exhibited strong FOXL2 and weak SMAD4 binding in gel shift assays. SMAD4, but not FOXL2, directly bound the other distal enhancer. Mutation of defined FOXL2 and SMAD4 cis-elements diminished enhancer activity in reporter assays in LβT2 cells. Collectively, the data indicate that there may be as many as 4 activin-sensitive enhancers upstream of murine Fshb.

Animals↗
PubMed2025

Innate immune molecular landscape following controlled human influenza virus infection.

Viral infections can induce prolonged changes in innate immunity. Here, we use blood samples from a human influenza H3N2 challenge study (NCT03883113) to perform comprehensive multi-omics analyses. We detect remodeling of immune programs in circulating innate immune cells that persist after resolution of the infection. We find changes associated with suppressed inflammation, including decreased cytokine and AP-1 gene expression as well as decreased accessibility at AP-1 targets and interleukin-related gene promoter regions. We also find decreased histone deacetylase gene expression, increased MAP kinase gene expression, and increased accessibility at interferon-related gene promoter regions. Genes involved in inflammation and methylation remodeling show modulation of gene-chromatin site regulatory circuit activity. These results reveal a coordinated rewiring of the molecular landscape in innate immune cells induced by mild influenza virus infection.

Humans↗
PubMed2024

Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures.

Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs.

Animals↗