Biology subjects

Thiriveedi, V.

Publications and source records attributed to Thiriveedi, V..

3 recordsLinked to original sources

bioRxiv2026

Aging restricts colorectal tumor growth by epigenetically silencing developmental gene programs

The incidence of early-onset colorectal cancer (CRC) has risen sharply in recent decades1, yet the biological basis underlying the distinct behavior of tumors arising in young versus aged tissues remains poorly understood. Here we show that aging reprograms the epigenetic landscape of the colon, restricting colon tumor growth through stable silencing of developmental and fetal gene programs. We find that colon tumors arising in aged mice are intrinsically less proliferative than those arising in young animals. Multi-omic profiling of normal colon and colon tumors reveals that aging drives DNA hypermethylation, loss of Polycomb-associated chromatin states, and reduced chromatin accessibility at a defined set of developmental genes that are bivalent (marked by both H3K27me3 and H3K4 methylation), transcriptionally active in colon tumors from young animals and repressed in both tumors and normal tissue from old animals. Among the genes most strongly repressed in old animals is Tacstd2 (Trop2), a regulator of fetal intestinal programs and epithelial stemness. Pharmacologic inhibition of DNA methylation reactivates the aging-silenced gene network in organoids from old animals, whereas genetic disruption of Tacstd2 suppresses growth and developmental transcriptional programs in young tumor organoids. TACSTD2, fetal gene signatures, and the aging-associated bivalent gene program are likewise repressed in late-onset vs. early-onset human colorectal cancers. Collectively, these findings identify age-associated epigenetic silencing of developmental gene programs as a causal mechanism that constrains colorectal tumor growth and provide a mechanistic framework for understanding the distinct biology of early-onset colorectal cancer.

cancer biology↗

bioRxiv2026

O-GlcNAcylation regulates PPAR-driven metabolic programming in intestinal stem cells

Diet deeply influences health and disease risk by reshaping cellular metabolism. In the intestine, dietary nutrients directly affect intestinal stem cell (ISC) behavior, yet the regulatory mechanisms linking metabolism to transcriptional control remain poorly defined. Because mitochondria function as central metabolic hubs, we focused on mitochondrial signaling to understand how nutrient utilization governs ISC function. Using the MITO-Tag mouse, we isolated metabolites specifically from ISC mitochondria and found that the sugar-derived metabolite UDP-GlcNAc was reduced in ISCs from mice fed a high-fat diet. Moreover, we identified that reducing O-GlcNAcylation (OGN) rapidly increased stem cell frequency, proliferation, regenerative capacity, and the abundance of PPAR target proteins. Mechanistically, these effects depend on PPAR signaling, as genetic loss of Ppar-d/a blocks the ISC phenotypes induced by reduced OGN. These results reveal an OGN-PPAR signaling axis that translates dietary metabolic cues into transcriptional programs governing fuel utilization and ISC behavior in the intestine. Collectively, our findings highlight that OGN is a previously unrecognized regulator of PPAR signaling in intestinal stem cells.

cell biology↗

bioRxiv2022

The Intestine is a Major Contributor to Circulating TCA Cycle Intermediates in Mice

The tricarboxylic acid (TCA) cycle is the epicenter of cellular aerobic metabolism. TCA cycle intermediates facilitate energy production and provide anabolic precursors, but also function as intra- and extracellular metabolic signals regulating pleiotropic biological processes. Despite the importance of circulating TCA cycle metabolites as signaling molecules, the source of circulating TCA cycle intermediates remains uncertain. We observe that in mice, the concentration of TCA cycle intermediates in the portal blood exceeds that in tail blood indicating that the gut is a major contributor to circulating TCA cycle metabolites. With a focus on succinate as a representative of TCA cycle intermediate with signaling activities and using a combination of germ-free mice and isotopomer tracing, we demonstrate that intestinal microbiota are not major contributors to circulating TCA cycle metabolites. Moreover, we demonstrate that the endogenous succinate production is markedly higher than intestinal succinate absorption in normal physiological conditions. Altogether, these results indicate that endogenous succinate production within the intestinal tissue is a major physiological source of circulating succinate. These results provide a foundation for investigation into the role of intestine in regulating circulating TCA cycle metabolites and related signaling effects in health and disease.

physiology↗