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The Diabetes Gene Tcf7l2 Organizes Gene Expression in the Liver and Regulates Amino Acid Metabolism

GSE298551 Mus musculus Expression profiling by high throughput sequencing 4 samples Submitted 2025/08/06 Platform GPL24247
Summary
TCF7L2 harbors the strongest genetic association with diabetes identified thus far. However, its function in liver has remained unclear. Here, we find using mice with liver-specific deletion, that Tcf7l2 plays a central role in maintaining hepatic zonation. That is, in the normal liver, many genes show gradients of expression across the liver lobule; in the absence of Tcf7l2, these gradients collapse. One major consequence is the disorganization of glutamine metabolism, with a loss of the glutamine production program, ectopic expression of the glutamine consumption program, and a decrease in glutamine levels. In parallel, metabolomic profiling shows glutamine to be the most significantly decreased metabolite in individuals harboring the rs7903146 variant in TCF7L2. Taken together, these data indicate that hepatic TCF7L2 has a secondary role in glycemic control, but a primary role in maintaining transcriptional architecture and glutamine homeostasis.
Published in
The diabetes gene Tcf7l2 organizes gene expression in the liver and regulates amino acid metabolism
Krawczyk J, O'Connor W, Vendramini P et al. · Molecular metabolism 2025 · PMID 40675550 · doi:10.1016/j.molmet.2025.102208
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Also filed as BioProject PRJNA1269928 and SRA study SRP589017. Searching any of these in the dataset finder brings you back here.

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