Biology subjects

Festing, M. H.

Publications and source records attributed to Festing, M. H..

3 recordsLinked to original sources

bioRxiv2026

HAT1 Regulates Intestinal Stem Cell Proliferation and Differentiation

Stem cells are critical for the development and maintenance of tissue integrity. An important example is intestinal stem cells (ISCs) that generate all epithelial cell types necessary for formation of the intestinal lining. HAT1, a histone acetyltransferase that acetylates newly synthesized histone H4 molecules on lysine residues 5 and 12 during replication-coupled chromatin assembly, is specifically expressed in intestinal stem and progenitor cells located in intestinal crypts. To determine if HAT1 is important for intestinal stem and progenitor cell function, we generated an inducible deletion of the HAT1 gene in intestinal epithelial cells. Loss of HAT1 resulted in morphological defects in the proximal end of the small intestine. Following loss of HAT1, intestinal crypts became elongated, with an increase in stem and progenitor cell proliferation and an increase in the population of OLFM+ cells. Loss of HAT1 also resulted in alterations in intestinal stem cell differentiation, including an increase in the number of Goblet cells and the mislocalization of Paneth cells into villi. HAT1 is specifically responsible for the acetylation of histone H4 lysine 5 (H4K5ac) in intestinal stem cells. Genome-wide characterization of HAT1-dependent H4K5ac in intestinal crypt cells indicates that the most significant loss of H4K5ac occurs in lamina-associated domains (LADs). Loss of H4K5ac in LADs is accompanied by an increase in histone H3 K9 tri-methylation indicating that HAT1 regulates LAD chromatin structure in intestinal crypt cells. A direct role for HAT1 in intestinal stem cell function was demonstrated using organoids in culture. HAT1 is required for differentiation in organoids and for the maintenance of Lgr5+ stem cells. These results indicate that HAT1 is required for the proper regulation of intestinal stem cell renewal and differentiation.

cell biology↗

bioRxiv2025

Gasdermin C links nutrient and immune signaling to protist-induced type 2 immunity and intestinal repair

The Gasdermin family of proteins has recently been implicated in tissue repair and homeostasis through their effector function in type 2 immunity and pyroptosis. Yet the role of Gasdermin C proteins has not been fully characterized in the mammalian intestine, where environmental factors can influence epithelial regeneration and repair. Here we report that Gsdmc2-4 genes are regulated in a nutrient-dependent manner and are suppressed with aging. We uncover that commensal protists in the gut regulate Gsdmc2-4 expression through activation of type 2 immune responses. In intestinal organoid experiments, we find that STAT6 is necessary for Gsdmc2-4 induction in response to type 2 cytokines; however, basal expression of Gsdmc2-4 in vivo is only partially diminished in Stat6 knockout animals. Finally, in protist-colonized animals, loss of Gsdmc1-4 exacerbated mucosal erosion and inflammation in response to Dextran sodium sulfate (DSS) exposure, implicating these proteins in coordinating epithelial responses to injury.

physiology↗

bioRxiv2025

Stearoyl-CoA Desaturases regulate stem and progenitor cell metabolism and function in response to nutrient abundance

Dietary components and metabolites play a critical role in regulating intestinal stem and progenitor cell function and proliferation. Here we show that Stearoyl-CoA Desaturases (SCDs), which regulate intracellular saturated to monounsaturated fatty acids ratios, are induced in response to nutrient abundance, especially in the distal intestine, and regulate intestinal homeostasis. Genetic or pharmacological inhibition of SCDs altered lipid metabolism, increased ER stress, and reduced proliferative intestinal stem and progenitor cells in intestinal organoids. These effects were largely mitigated by oleic acid supplementation. Intestinal epithelium-specific deletion of Scd1 and Scd2 led to metabolic rewiring, leading to expansion of progenitor cell populations. DSS-induced epithelial damage revealed a dependence on SCD enzymes during regeneration, accelerating epithelial damage and inflammation in intestines lacking epithelial Scd1 and Scd2. These findings underscore key metabolic pathways and dependencies that enable intestinal stem and progenitor cells to adapt to nutrient fluctuations and support epithelial tissue regeneration following injury.

physiology↗