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PubMed · 40120584

Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation.

Vanessa Lopez-Pajares·Aparna Bhaduri·Yang Zhao·Gayatri Gowrishankar·Laura K H Donohue·Margaret G Guo·Zurab Siprashvili·Weili Miao·Duy T Nguyen·Xue Yang·Albert M Li·Alan Sheng-Hwa Tung·Ronald L Shanderson·Marten C G Winge·Lindsey M Meservey·Suhas Srinivasan·Robin M Meyers·Angela Guerrero·Andrew L Ji·Omar S Garcia·Shiying Tao·Sanjiv S Gambhir·Jonathan Z Long·Jiangbin Ye·Paul A Khavari
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Abstract

Non-energetic roles for glucose are largely unclear, as is the interplay between transcription factors (TFs) and ubiquitous biomolecules. Metabolomic analyses uncovered elevation of intracellular glucose during differentiation of diverse cell types. Human and mouse tissue engineered with glucose sensors detected a glucose gradient that peaked in the outermost differentiated layers of the epidermis. Free glucose accumulation was essential for epidermal differentiation and required the SGLT1 glucose transporter. Glucose affinity chromatography uncovered glucose binding to diverse regulatory proteins, including the IRF6 TF. Direct glucose binding enabled IRF6 dimerization, DNA binding, genomic localization, and induction of IRF6 target genes, including essential pro-differentiation TFs GRHL1, GRHL3, HOPX, and PRDM1. These data identify a role for glucose as a gradient morphogen that modulates protein multimerization in cellular differentiation.

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Cell DifferentiationAnimalsHumansGlucoseMiceInterferon Regulatory FactorsProtein MultimerizationEpidermisTranscription FactorsEpidermal CellsIRF6differentiationglucoseJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, U.S. Gov't, Non-P.H.S.

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Vanessa Lopez-Pajares, Aparna Bhaduri, Yang Zhao, Gayatri Gowrishankar, Laura K H Donohue, Margaret G Guo, Zurab Siprashvili, Weili Miao, Duy T Nguyen, Xue Yang, Albert M Li, Alan Sheng-Hwa Tung, Ronald L Shanderson, Marten C G Winge, Lindsey M Meservey, Suhas Srinivasan, Robin M Meyers, Angela Guerrero, Andrew L Ji, Omar S Garcia, Shiying Tao, Sanjiv S Gambhir, Jonathan Z Long, Jiangbin Ye, Paul A Khavari. 2025-03-21. Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation.. https://doi.org/10.1016/j.stem.2025.02.017

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