Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation
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.
Authors
- Shiying Tao
- Paul A. Khavari (ORCID: https://orcid.org/0000-0003-0098-4989)
- Andrew L. Ji (ORCID: https://orcid.org/0000-0001-9688-5680)
- Sanjiv S. Gambhir (ORCID: https://orcid.org/0000-0002-2711-7554)
- Margaret Guo (ORCID: https://orcid.org/0000-0001-7713-3846)
- Laura K. Donohue (ORCID: https://orcid.org/0000-0002-1346-2840)
- Suhas Srinivasan (ORCID: https://orcid.org/0000-0001-8309-9648)
- Jonathan Z. Long (ORCID: https://orcid.org/0000-0003-2631-7463)
- Alan Sheng-Hwa Tung (ORCID: https://orcid.org/0000-0002-0669-1928)
- Gayatri Gowrishankar (ORCID: https://orcid.org/0000-0002-9161-2701)
- Jiangbin Ye (ORCID: https://orcid.org/0000-0003-1117-4869)
- Xue Yang (ORCID: https://orcid.org/0000-0002-1288-5569)
- Weili Miao (ORCID: https://orcid.org/0000-0002-7487-8962)
- Duy T. Nguyen (ORCID: https://orcid.org/0000-0001-6570-6010)
- Aparna Bhaduri (ORCID: https://orcid.org/0000-0003-4625-6899)
- M.C.G. Winge (ORCID: https://orcid.org/0000-0001-6119-6009)
- Vanessa Lopez-Pajares (ORCID: https://orcid.org/0000-0001-8538-344X)
- Robin M. Meyers (ORCID: https://orcid.org/0000-0002-1802-7231)
- Albert M. Li (ORCID: https://orcid.org/0000-0002-0865-6915)
- Zurab Siprashvili (ORCID: https://orcid.org/0000-0002-2814-4220)
- Omar S. Garcia
- Ronald L. Shanderson (ORCID: https://orcid.org/0000-0002-9702-2972)
- A. Guerrero (ORCID: https://orcid.org/0009-0007-1498-5049)
- Lindsey M. Meservey (ORCID: https://orcid.org/0000-0001-9436-7185)
- Yang Zhao (ORCID: https://orcid.org/0000-0002-4303-1240)
Institutions
- VA Palo Alto Health Care System (US)
- Stanford Medicine (US)
- Stanford University (US)
Publication Details
- Journal
- Cell stem cell
- Published
- 2025-03-22
- DOI
- https://doi.org/10.1016/j.stem.2025.02.017
- Citations
- 9
- Primary Topic
- Cancer-related Molecular Pathways
- Type
- article
- Field-Weighted Citation Impact
- 9.41
Funders
- U.S. Department of Veterans Affairs
- National Institute of Arthritis and Musculoskeletal and Skin Diseases