Biology subjects

Sampson, S.

Publications and source records attributed to Sampson, S..

3 recordsLinked to original sources

bioRxiv2025

MAPK/ERK signaling blocks ectopic H3K9me3 heterochromatin formation to confer mesoderm and endoderm developmental competence

During gastrulation, dynamic interplay among cell signaling pathways dictates cell fate decisions. While extensive studies have elucidated their critical roles in morphological regulation, how these signals orchestrate the epigenome to confer developmental competence remains unclear. In this study, we demonstrate that H3K9me3-marked facultative heterochromatin domains undergo global reorganization during differentiation of human pluripotent stem cells into mesoderm and endoderm, which arise through epithelial-mesenchymal transition (EMT), but not into ectoderm, which retains epithelial state. We identify the MAPK/ERK pathway, acting downstream of FGF signaling, as a key mediator of this reorganization. Specifically, the MAPK/ERK pathway prevents ectopic formation of H3K9me3 domains at EMT- and lineage-specific gene loci whose expression is necessary for mesoderm and endoderm differentiation. Collectively, our findings reveal a previously unrecognized role for MAPK/ERK signaling in reorganizing the H3K9me3 landscape to enable mesoderm and endoderm differentiation, bridging a critical gap in our knowledge of how cell signaling pathways shape the epigenetic landscape during development.

developmental biology↗

bioRxiv2024

The Deubiquitinating Enzyme Otub2 Modulates Pancreatic Beta-Cells Function and Survival

We have previously shown that otubain 2 (OTUB2), a deubiquitinating enzyme, inhibits caspase-3/7 activity in primary human islets; promotes insulin secretion and inhibits cytokine-induced nuclear factor-{kappa}B (NF{kappa}B) activity. In the present work we show that overexpression of Otub2 in MIN6 cells inhibits NF{kappa}B activity and the expression of its target genes MCP-1 and iNOS. Consequently, both the basal and the cytokine-induced apoptosis of cultured MIN6 cells and dispersed human islets were inhibited. Overexpression of Otub2 in MIN6 cells increase the mRNA levels of NKx6.1 and Glut2 and concomitantly increased glucose-stimulated insulin secretion (GSIS) (by 2-3-fold). The beneficial effects of Otub2 on {beta}-cell function was demonstrated by the phenotype of Otub2-/+ and Otub2-/- mice, which manifested impaired glucose tolerance and increased expression of NFkB target genes (e.g. IP-10, MCP-1 and IL-1{beta}). RNAseq analysis of pancreata derived from OTUB2 KO mice revealed reduced expression of genes that down regulate K+ transporters (e.g. Ank2, Cacna1a and Kcnab1) combined with an increase in oxidative phosphorylation related genes. Given that closure of K+ channels is crucial for insulin secretion, these results could account, at least in part, for the impaired GSIS in the OTUB2 KO mice. Indeed, mass-spectrometry analysis of proteins co-immunoprecipitated with Otub2 revealed the voltage-gated potassium channel subunit Kv9.3 as a major Otub2 binding-partner. Additional binding partners included the Peg3 and Camk2d proteins, which promote NF{kappa}B signaling and {beta}-cell death. Hence, by deubiquitinating proteins in complexes that contain Peg3 and Camk2d, Otub2 might inhibit propagation of NF{kappa}B signaling and {beta}-cell apoptosis. Collectively our findings implicate Otub2 as a key regulator of {beta} cell function, mainly affecting NFkB signaling and the K+ channels that regulate insulin secretion.

cell biology↗

bioRxiv2022

Impact of the extinct megaherbivore Steller's sea cow (Hydrodamalis gigas) on kelp forest resilience

Giant kelp forests off the west coast of North America are maintained primarily by sea otter (Enhydra lutris) and sunflower sea star (Pycnopodia helianthoides) predation of sea urchins. Human hunting of sea otters in historic times, together with a marine heat wave and sea star wasting disease epidemic in the past decade, have devastated these predators, leading to widespread occurrences of urchin barrens. Since the late Neogene, species of the megaherbivorous sirenian Hydrodamalis ranged throughout North Pacific giant kelp forests. The last species, H. gigas, was driven to extinction by human hunting in the mid-18th century. H. gigas was an obligate kelp canopy browser, and its body size implies that it would have had a significant impact on the system. Here we hypothesize that sea cow browsing would have promoted a denser understory algal assemblage than is typical today, thereby providing an alternative food resource for urchins, resulting in enhanced forest resilience. We tested this hypothesis with a mathematical model, comparing historical and modern community responses to marine heat waves, sea star wasting disease, and the presence of sea otters. We found that forest communities were highly resistant to marine heat waves, yet susceptible to sea star wasting disease, and to disease in combination with warming. Resistance was greatest among systems with both sea cows and sea otters present. Most simulations that transitioned to barrens did so temporarily, recovering after about 10 years. Historical communities, however, exhibited delayed transitions after perturbation relative to modern communities and faster recovery times. Sea cow browsing facilitated denser algal understories, enhancing resilience against modern perturbations. We propose that operationalizing these findings by mimicking the ecological impact of sea cow herbivory could enhance kelp forest resilience.

ecology↗