Biology subjects

Gates, L. A.

Publications and source records attributed to Gates, L. A..

5 recordsLinked to original sources

bioRxiv2026

Starvation improves epithelial fitness by selectively extruding DNA damaged cells

During homeostasis, crowded cells with the lowest energy levels are eliminated by extrusion via Piezo1 signalling to maintain constant cell numbers. However, crowding-induced extrusion does not necessarily remove damaged or otherwise unfit cells. Here, we show that glucose or glutamine starvation triggers a rapid, regulated wave of extrusion, called starvation-induced cell extrusion (STICE), that selectively eliminates cells bearing DNA damage markers via a p53-dependent, Piezo1-independent pathway, improving monolayer fitness. Unlike non-extruding cells, which recycle contents through autophagy and lysosomal digestion, p53-activated cells instead use LC3 to drive lysosomal exocytosis, promoting extrusion signalling. By eliminating defective and transformed cells, STICE confers resistance to damage and apoptotic stimuli in the remaining monolayer. STICE thus acts as a tissue-level analogue of autophagy: rather than improving individual cells by digesting and recycling damaged components, it improves tissue fitness by eliminating substandard cells.

cell biology↗

bioRxiv2026

Multiomic screening platform uncovers the impact of histone mutations on chromatin and cell fate

Somatic missense mutations in histone genes, often referred to as oncohistones, have been identified in diverse types of human cancers. The functional and mechanistic impact of most oncohistones remains unknown. To address this gap, we developed CHANCLA, a modular platform for high-throughput functional screening of oncohistones using multiomic phenotypic readouts. We used CHANCLA to systematically measure the impact of 303 human oncohistones on cellular proliferation, differentiation, histone-specific post-translational modifications, and chromatin accessibility. Integrative multiomic analyses revealed discrete oncohistone molecular classes that promote proliferation, block lineage-specific differentiation, and physically remodel the chromatin landscape by altering specific histone modifications and reducing nucleosome stability. Structural mapping and computational modeling studies uncovered that functionally convergent mutations are clustered at key nucleosome interfaces, particularly H2B-H4, and that chromatin accessibility-promoting mutations are linked to mono-nucleosome destabilization. Leveraging this multiomic resource, we discovered that the H3.3-Q5H mutant histone is a bona fide human oncohistone that accelerates lung adenocarcinoma growth in vivo. Mechanistically, we found that H3.3-Q5H expression leads to suppression of promoter-associated H3K4me3 and expansion of repressive H3K27me3 domains, resulting in increased KRAS signaling and gene expression programs associated with epithelial-to-mesenchymal transition. Together, this work provides a multiomic functional atlas of cancer-associated histone mutations, identifies structural and mechanistic principles governing chromatin reprogramming by oncohistones, and establishes CHANCLA as a modular platform for systematic discovery of mechanisms and vulnerabilities associated with these genetic lesions.

cancer biology↗

bioRxiv2025

Short chain fatty acids regulate the chromatin landscape and distinct gene expression changes in human colorectal cancer cells

Short chain fatty acids (SCFAs) are small metabolites that are produced through the activity of microbes and have important roles in human physiology. These metabolites have varied mechanisms in interacting with the host, of which one such mode is decorating the chromatin landscape. We previously detected specific histone modifications in the mouse gut that can be derived from SCFAs and are regulated by the microbiota. However, the roles of these SCFAs on chromatin and how they impact gene regulation in human cells is largely unknown. Now, our studies demonstrate these microbiota-dependent histone posttranslational modifications (PTMs) are associated with alterations in gene regulation in human cells. We show that histone butyrylation on H3K27 is detected in human colon samples. Furthermore, histone acetylation, butyrylation, and propionylation on H3K9 and H3K27 are responsive to levels of SCFAs in human colon cancer cell lines and are associated with active gene regulatory elements. In addition, treatment of human cancer cell lines with individual metabolites or combinations of SCFAs replicating the intestinal lumen environment result in distinct and overlapping gene program changes, with butyrate largely driving gene regulatory effects of SCFA combinations. Lastly, we define butyrate effects on gene expression that are independent of HDAC inhibition and are dependent on p300/CBP, suggesting potential gene programs regulated by histone butyrylation. Together, these results demonstrate that SCFAs are key regulators of the chromatin landscape and gene programs in human colorectal cancer cells.

cell biology↗

bioRxiv2022

Microbiota-dependent histone butyrylation in the mammalian intestine

Posttranslational modifications (PTMs) on histone proteins are a key source of regulation on chromatin through impacting genome organization and important cellular processes, including gene expression. These PTMs often arise from small metabolites and are thus impacted by cellular metabolism and environmental cues. One such class of metabolically regulated PTMs are histone acylations, which include histone acetylation, along with butyrylation, crotonylation, and propionylation. We asked whether histone acylations of intestinal epithelial cells (IECs) are regulated through the availability of short chain fatty acids (SCFAs), which are generated by the commensal microbiota in the intestinal lumen. We identified IECs from the cecum and distal mouse intestine as sites of high levels of histone acylations, including histone butyrylation and propionylation. We identified specific sites of butyrylation and propionylation on lysine 9 and 27 on histone H3. We demonstrate that these acylations are regulated by the microbiota, whereas histone butyrylation is additionally regulated by the metabolite tributyrin. Furthermore, we identify tributyrin-regulated gene programs that correlate with histone butyrylation and demonstrate that histone butyrylation (H3K27bu) is associated with active gene regulatory elements and levels of gene expression. Together, our observations demonstrate a physiological setting in which previously uncharacterized histone acylations are dynamically regulated and associated with gene expression.

molecular biology↗

bioRxiv2021

Stable Isotope Tracing In Vivo Reveals A Metabolic Bridge Linking The Microbiota To Host Histone Acetylation

The gut microbiota influences host epigenetics by fermenting dietary fiber into butyrate. Although butyrate could promote histone acetylation by inhibiting histone deacetylases, it may also undergo oxidation to acetyl-CoA, a necessary cofactor for histone acetyltransferases. Here, we find that epithelial cells from germ-free mice harbor a loss of histone H4 acetylation across the genome except at promoter regions. Using stable isotope tracing in vivo with 13C-labeled fiber, we demonstrate that the microbiota supplies carbon for histone acetylation. Subsequent metabolomic profiling revealed hundreds of labeled molecules and supported a microbial contribution to host fatty acid metabolism, which declined in response to colitis and correlated with reduced expression of genes involved in fatty acid oxidation. These results illuminate the flow of carbon from the diet to the host via the microbiota, disruptions to which may affect energy homeostasis in the distal gut and contribute to the development of colitis.

biochemistry↗