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bioRxiv · 10.1101/2023.12.31.573781

Transient BRD4 degradation improves cardiac reprogramming by inhibiting macrophage/Oncostatin M induced JAK/STAT pathway

Liu, L.·Guo, Y.·Tian, S.·Lei, I.·Gao, W.·Li, Z.·Wang, S.·Chen, E.·Wang, Z.
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Abstract

Reprogramming fibroblasts into induced cardiomyocytes (iCMs) holds great potential for cardiac regeneration. However, low conversion rate both in vitro and in vivo remains a significant challenge. To address this challenge, we focused on potential epigenetic barriers and screened 33 small-molecule inhibitors/degraders targeting histone acetyl post-translational modifications and related epigenetic factors. BET degraders were found to enhance cardiac reprogramming efficiency by degrading BRD4 and repressing genes involved in immune response, particularly those in the JAK/STAT pathway. We further identified that macrophage/oncostatin M activated the JAK/STAT pathway to repress cardiac reprogramming. BRD4 degrader treatment improved iCMs formation by inhibiting macrophage/oncostatin M-induced activation of the JAK/STAT pathway. Moreover, BRD4 degrader treatment enhanced MGT-mediated cardiac regeneration in vivo and improved myocardial performance post-myocardial infarction. These findings provide new insights into BRD4, macrophage/oncostatin M and JAK/STAT pathway in fibroblast to cardiomyocyte-like cell conversion and offer promising targets and small molecules to improve iCM reprogramming for clinical applications. HighlightsO_LIScreen of histone acetylation modifiers identified BRD4, a histone acetylation reader, as an important regulator in cardiac reprogramming. C_LIO_LIBRD4 degradation promoted cardiac reprogramming by repressing inflammation and the JAK-STAT pathway. C_LIO_LIBRD4 degradation inhibited macrophage/oncostatin M-induced activation of the JAK/STAT pathway. C_LIO_LIBRD4 degradation enhanced MGT-mediated cardiac regeneration in vivo and improved myocardial performance post-myocardial infarction. C_LI

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Liu, L., Guo, Y., Tian, S., Lei, I., Gao, W., Li, Z., Wang, S., Chen, E., Wang, Z.. 2024-01-01. Transient BRD4 degradation improves cardiac reprogramming by inhibiting macrophage/Oncostatin M induced JAK/STAT pathway. https://doi.org/10.1101/2023.12.31.573781

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