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Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation
Vanessa Lopez-Pajares1, Aparna Bhaduri2, Yang Zhao1
1Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Stem Cell
|March 22, 2025
Summary
Glucose acts as a morphogen, regulating cell differentiation. Intracellular glucose accumulation, essential for epidermal differentiation, enables transcription factor dimerization and gene induction.
Area of Science:
- Cell Biology
- Biochemistry
- Developmental Biology
Background:
- The non-energetic functions of glucose and its interactions with transcription factors (TFs) are not well understood.
- Cellular differentiation involves complex regulatory networks influenced by various biomolecules.
Purpose of the Study:
- To investigate the role of intracellular glucose accumulation in cellular differentiation.
- To elucidate the molecular mechanisms by which glucose influences transcription factor activity and gene expression.
Main Methods:
- Metabolomic analysis of differentiating cell types.
- Engineering human and mouse tissues with glucose sensors to detect glucose gradients.
- Glucose affinity chromatography to identify glucose-binding proteins.
- Assays to study transcription factor dimerization, DNA binding, and genomic localization.
Main Results:
- Intracellular glucose levels increase during differentiation across various cell types.
- A glucose gradient was observed in engineered human and mouse tissues, peaking in differentiated epidermal layers.
- SGLT1 transporter activity was crucial for glucose accumulation and epidermal differentiation.
- Glucose directly binds to the IRF6 transcription factor, promoting its dimerization, DNA binding, and the induction of key differentiation genes (GRHL1, GRHL3, HOPX, PRDM1).
Conclusions:
- Glucose functions as a gradient morphogen, influencing cellular differentiation.
- Glucose binding to transcription factors modulates their activity, impacting gene regulation during differentiation.
- This study reveals a novel mechanism where a ubiquitous metabolite directly controls developmental processes.
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