Biology subjects

Thai, C.

Publications and source records attributed to Thai, C..

3 recordsLinked to original sources

bioRxiv2025

A dietary pan-amino acid dropout screen in vivo reveals a critical role for histidine in T-ALL

Dietary interventions show therapeutic potential in cancer, but systematic comparisons are lacking. We performed a dietary pan-amino acid dropout screen in an orthotopic model of NOTCH1-driven T-cell acute lymphoblastic leukemia and identified histidine depletion as uniquely antileukemic. Histidine-restricted diets extended survival of leukemic mice in a dose-dependent manner, while remaining well-tolerated. Mechanistically, multiomic profiling revealed that histidine deprivation-induced ribosome stalling activates GCN2 to suppress cholesterol biosynthesis pathways critical for leukemic proliferation. Dietary cholesterol supplementation partially reverted the antileukemic effects of histidine restriction in vivo. These findings couple histidine levels and translational control to cholesterol metabolism, which can be therapeutically exploited for cancer treatment. Our results suggest that defined dietary amino acid restrictions may expose broader therapeutic opportunities in diseases beyond cancer.

cancer biology↗

bioRxiv2025

Guiding clustering and annotation in single-cell RNA sequencing using the average overlap metric

Defining cell types using unsupervised clustering algorithms based on transcriptional similarity is a powerful application of single-cell RNA sequencing. A single clustering resolution may not yield clusters that represent both broad, well-defined populations and smaller subpopulations simultaneously. Therefore, when cell identities are not known prior to sequencing, robust comparison and annotation of inferred de novo clusters remains a challenge. In this work, we define the distance between single-cell clusters by proposing the use of the average overlap metric to compare ranked lists of differentially expressed genes in a top-weighted manner. We first benchmark our approach in a truth-known dataset comprised of highly similar yet distinct T-cell populations and show that evaluating clusters with average overlap results in a consistent, precise, and biologically meaningful recapitulation of true cell identities. We then apply our approach to data of unsorted mouse thymocytes and characterize stages of T-cell development in the thymus, including minor populations of double-negative (CD4-CD8-) T-cells that are notoriously difficult to confidently detect in unsorted single-cell data. We demonstrate that measuring cluster similarity with average overlap of marker gene rankings enables robust, reproducible characterization of single cells and clarifies biological interpretation of their underlying identities in highly homogeneous populations.

bioinformatics↗

bioRxiv2018

Hyperinsulinemia promotes aberrant histone acetylation in triple negative breast cancer

Excess levels of insulin relative to glucose in the blood, or hyperinsulinemia, is considered to be a poor prognostic indicator for patients with triple negative breast cancer (TNBC). While this association has been recognized for some time, the mechanistic role of hyperinsulinemia in promoting TNBC remains unclear. We show that insulin treatment leads to genome-wide increase in histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway in MDA-MB-231 cells. Genome-wide analysis showed that the increase in histone acetylation occurs primarily at gene promoters. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. In vivo, hyperinsulinemia also enhances growth of MDA-MB-231 derived tumors through increased histone acetylation. These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.

molecular biology↗