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Transcriptome changes with GSK-J4 treatment in an ex vivo post-cataract surgery model

ABSTRACT: Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzyme UTX creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure. This period of decondensed nascent chromatin structure allows for binding of pro-fibrotic transcription factor, MRTF-A to nascent DNA. Inhibition of UTX enzymatic activity condenses chromatin structure, prevents MRTF-A binding, blocks activation of the pro-fibrotic transcriptome, and results in an inhibition of fibrosis in lens and lung fibrosis models. Our work reveals UTX as a central coordinator of fibrosis, highlighting the potential to target its demethylase activity to prevent organ fibrosis.

ORGANISM(S): Gallus gallus

PROVIDER: GSE213480 | GEO | 2022/09/20

REPOSITORIES: GEO

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Alternative mRNA splicing controls functions of the human H3K27 demethylase UTX/KDM6A

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