Abstract P324: Brd4 Degradation Enhances Cardiac Reprogramming And Regeneration By Inhibiting JAK/STAT Pathway

• Published in: Circulation research Vol. 129; no. Suppl_1
• Main Authors: Liu, Liu, Guo, Yijing, Lei, Ienglam, Tian, Shuo, Gao, Wenbin, Wang, Zhong
• Format: Journal Article
• Language: English
• Published: 03.09.2021
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.129.suppl_1.P324

Abstract only Reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a potentially promising strategy for regenerating a damaged heart. However, low conversion rate of fibroblasts to cardiomyocytes and poor in vivo application efficacy are major challenges in this reprogramming process. To address this issue, we attempted to identify small molecules related to histone acyl post-translational modifications that could enhance the reprogramming ability towards cardiac fate. Using α-muscle heavy chain-GFP-tagged mouse embryo fibroblasts as a starting cell type, we screened 46 inhibitors target histone acyl post-translational modifications and related epigenetic factors and identified an important role of Brd4 in modulating iCM reprogramming. In particular, we observed that a novel Brd4 degrader repressed many genes involved in immune responses especially JAK/STAT pathway. Mechanically, Brd4 degrader repressed JAK/STAT related gene expressions by affecting Brd4 binding to promoters of those genes. More importantly, Brd4 degrader treatment enhanced MGT induced cardiac regeneration in vivo and markedly improved myocardial performance after myocardial infarction. These findings shed new light on the molecular mechanisms underlying the cardiac conversion of fibroblasts and provide novel targets and small molecules to improve iCM reprogramming for clinical applications.