Changes in Nascent Chromatin Structure Regulate Activation of the Pro-fibrotic Transcriptome and Myofibroblast Emergence in Organ Fibrosis

Authors

Morgan D. Basta, Thomas Jefferson UniversityFollow
Svetlana Petruk, Thomas Jefferson UniversityFollow
Ross Summer, Thomas Jefferson UniversityFollow
Joel Rosenbloom, Thomas Jefferson UniversityFollow
Peter J. Wermuth, Thomas Jefferson UniversityFollow
Edward J. Macarak, Thomas Jefferson UniversityFollow
Alex V. Levin, Thomas Jefferson UniversityFollow
Alexander Mazo, Thomas Jefferson UniversityFollow
Janice L. Walker, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

5-19-2023

Comments

This article is the author’s final published version in iScience, Volume 26, Issue 5, May 2023, Article number 106570.

The published version is available at https://doi.org/10.1016/j.isci.2023.106570. Copyright © Basta et al.

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 enzymes UTX/KDM6B 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, Myocardin-related transcription factor A (MRTF-A) to nascent DNA. Inhibition of UTX/KDM6B 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/KDM6B as central coordinators of fibrosis, highlighting the potential to target its demethylase activity to prevent organ fibrosis.

Recommended Citation

Basta, Morgan D.; Petruk, Svetlana; Summer, Ross; Rosenbloom, Joel; Wermuth, Peter J.; Macarak, Edward J.; Levin, Alex V.; Mazo, Alexander; and Walker, Janice L., "Changes in Nascent Chromatin Structure Regulate Activation of the Pro-fibrotic Transcriptome and Myofibroblast Emergence in Organ Fibrosis" (2023). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 237.
https://jdc.jefferson.edu/bmpfp/237

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Language

English