Amazing stuff!
"... [Glucose] by binding in its intact form to proteins that control which genes in the genome are made into proteins and when.
The discovery of glucose’s undercover double life was so surprising the researchers spent several years confirming their findings before publishing their results.
“At first we just didn’t believe it,” ... “But the results of extensive follow-up experiments were clear: Glucose interacts with hundreds of proteins throughout the cell and modulates their function to promote differentiation.” ...
They found that human skin organoids – engineered skin tissue grown in liquid that mimic the cellular composition and organization of native skin – were unable to differentiate properly when glucose levels were lower than normal. A closer look found that the expression of over 3,000 genes in the cells was affected by the low glucose levels; many of these genes encoded proteins known to be involved in skin differentiation. ...
found that glucose levels increase due to a boost in production of a protein that transports glucose from the outside of the cell to its interior. Once inside, glucose binds to hundreds of proteins, including one called IRF6, that increase the expression of many genes involved in differentiation. When glucose binds to IRF6, it causes the protein to change its conformation in a way that changes its ability to influence gene expression and drive differentiation. ..."
From the highlights and abstract:
"Highlights
• Intracellular free glucose accumulates during differentiation
• Elevation of free glucose is essential for epidermal differentiation
• Glucose physically associates with numerous proteins, including the IRF6 TF
• Glucose enables IRF6 dimerization, genomic localization, and target gene induction
Summary
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."
Graphical abstract:
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