EP300 as a Molecular Integrator of Fibrotic Transcriptional Programs

Abstract

Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, EP300-mediated acetylation of histones alters global chromatin structure and gene expression, promoting the development and progression of fibrosis. Here, we review the role of EP300-mediated epigenetic regulation in multi-organ fibrosis and its potential as a therapeutic target. We discuss the preclinical evidence that suggests that EP300 inhibition can attenuate fibrosis-related molecular processes, including extracellular matrix deposition, inflammation, and epithelial-to-mesenchymal transition. We also highlight the contributions of small molecule inhibitors and gene therapy approaches targeting EP300 as novel therapies against fibrosis.

CDK4/6 inhibitors in drug-induced liver injury: a pharmacovigilance study of the FAERS database and analysis of the drug–gene interaction network

“…HSP90AA1, a molecular chaperone involved in protein folding and stabilization, is potentially implicated in alcoholic hepatitis and cirrhosis ( Choudhury et al, 2020 ; Costa et al, 2020 ). EP300, a histone acetyltransferase, has been linked to multiorgan fibrosis through the TGFβ pathway, suggesting epigenetic regulation of fibrogenesis and progression ( Rubio et al, 2023 ). These findings provide avenues for future studies of the precise mechanisms by which CDK4/6 inhibitors influence these key molecular players in liver pathophysiology.…”

Epigenetic Regulation of EMP/EMT-Dependent Fibrosis

“…In particular, HATs regulate gene silencing or transcription through the modulation of the acetylation of histones, thus orchestrating gene expression to induce liver fibrosis [ 110 , 111 ]. Additionally, histone acetylation has been implied in pulmonary and cardiac fibrosis [ 10 ], performed through the activity of p300 HAT [ 112 , 113 ]. An interesting discovery enriched the molecular scenario by demonstrating that p300 HAT induces the fibrotic process in IPF and cardiac fibrosis via EMT and EndMT, respectively [ 114 ].…”

Epigenetic mechanisms of particulate matter exposure: air pollution and hazards on human health

“…Depending on the tissue, molecular characteristics, and grade of organ dysfunction, fibrosis is considered a life-threatening condition. Renal, cardiac, liver and pulmonary fibrosis are the major causes of death, but several studies have identified common altered epigenetic regulation that could be a potential approach to target multi-organ fibrosis ( Rubio et al, 2023b ). Particularly, pulmonary fibrosis (PF) is the irreversible phenotype of all interstitial lung diseases (ILDs), characterized by progressive thickening of lung tissue that reduces gas exchange and ultimately leads to progressive hypoxemia, respiratory failure, and mortality ( Zhu et al, 2023 ).…”