The Role of Post-Replicative Chromatin Structure in the Initiation and Progression of Fibrosis
Abstract
Fibrosis or scarring is characterized by the excessive accumulation of extracellular matrix (ECM) that leads to changes in tissue architecture and loss of organ function. Alpha smooth muscle actin (αSMA)-expressing myofibroblasts are recognized as the primary producers of excessive ECM in fibrosis. A lack in effective treatment options for fibrosis places a need to understand the underlying molecular mechanisms driving fibrotic disease. Here, we sought to understand 1) how myofibroblast precursor cells adopt a new pro-fibrotic transcription program in the initiation of fibrosis and 2) how myofibroblasts that have already acquired this fibrotic phenotype maintain a pro-fibrotic transcription program to drive the progression of fibrosis. In our investigations, we discovered transient windows of decondensed nascent chromatin structure at the time of DNA replication indicated by brief absence of the major repressive mark of condensed chromatin structure, histone 3 lysine 27 tri-methylated (H3K27me3). Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) and lysine demethylase 6B (KDM6B) demethylase enzymes are capable of demethylating H3K27me3 to loosen chromatin structure and were therefore implicated in creating this period of decondensed nascent chromatin structure. These brief periods of decondensed chromatin structure created by UTX and KDM6B allow for the adoption of pro-fibrotic transcription factors (TFs) to activate pro-fibrotic genes and drive fibrosis. Importantly, inhibiting UTX/KDM6B KDM activity with GSK-J4 condensed chromatin structure to block TF binding and prevent both the initiation and progression of fibrosis.
Subject Area
Cellular biology|Biochemistry|Developmental biology
Recommended Citation
Basta, Morgan D, "The Role of Post-Replicative Chromatin Structure in the Initiation and Progression of Fibrosis" (2023). ProQuest ETD Collection - Thomas Jefferson University. AAI30484949.
https://jdc.jefferson.edu/dissertations/AAI30484949
