生物
染色质
斑马鱼
H3K4me3
表观遗传学
增强子
转录因子
组蛋白
细胞生物学
再生(生物学)
二价染色质
基因表达调控
表观遗传学
染色质免疫沉淀
基因调控网络
遗传学
染色质重塑
基因
基因表达
发起人
DNA甲基化
作者
Julio Cordero,Adel Elsherbiny,Yinuo Wang,Lonny Jürgensen,Florian Constanty,Stefan Guenther,Melanie Boerries,Joerg Heineke,Arica Beisaw,Florian Leuschner,David Hassel,Gergana Dobreva
摘要
The limited regenerative capacity of the human heart contributes to high morbidity and mortality worldwide. In contrast, zebrafish exhibit robust regenerative capacity, providing a powerful model for studying how to overcome intrinsic epigenetic barriers maintaining cardiac homeostasis and initiate regeneration. Here, we present a comprehensive analysis of the histone modifications H3K4me1, H3K4me3, H3K27me3 and H3K27ac during various stages of zebrafish heart regeneration. We found a vast gain of repressive chromatin marks one day after myocardial injury, followed by the acquisition of active chromatin characteristics on day four and a transition to a repressive state on day 14, and identified distinct transcription factor ensembles associated with these events. The rapid transcriptional response involves the engagement of super-enhancers at genes implicated in extracellular matrix reorganization and TOR signaling, while H3K4me3 breadth highly correlates with transcriptional activity and dynamic changes at genes involved in proteolysis, cell cycle activity, and cell differentiation. Using loss- and gain-of-function approaches, we identified transcription factors in cardiomyocytes and endothelial cells influencing cardiomyocyte dedifferentiation or proliferation. Finally, we detected significant evolutionary conservation between regulatory regions that drive zebrafish and neonatal mouse heart regeneration, suggesting that reactivating transcriptional and epigenetic networks converging on these regulatory elements might unlock the regenerative potential of adult human hearts.
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