H3K27me3 deposition over sarcomeric and cytoskeletal promoters is required for cardiomyocyte cytokinesis and wound invasion during zebrafish heart regeneration [RNA-seq]

We identify the global transcriptional changes that occur between homeostatic and proliferative cardiomyocytes in the zebrafish heart and uncover an essential role for H3K27me3 deposition in facilitating successful myocardial regeneration. Specifically, we learned that cardiomyocyte proliferation is accompanied by downregulation of sarcomeric and cytoskeletal components and upregulation of the polycomb methylase Ezh2. Using ChIPseq, we demonstrate that this transcriptional repression is associated with deposition of new H3K27me3 modifications over the promoters. Using new genetic zebrafish lines that allow for inducible and cardiomyocyte-specific expression of a mutant form of histone 3 that is unable to be tri-methylated on lysine 27 (H3.3K27M), we discovered that addition of H3K27me3 marks is essential for cardiac regeneration in vivo. Earlier in the regenerative window, we found that H3.3K27M–expressing wound edge cardiomyocytes aberrantly maintain homeostatic levels of sarcomeric and actomyosin gene expression and show significant retention of sarcomere structure. While DNA replication occurs normally in these H3.3K27M cardiomyocytes, we observed significant increases in cardiomyocyte nucleation, a phenotype indicative of cytokinesis failures. In addition, nuclear density at the wound edge increases as new cardiomyocytes fail to colonize the injured area. Together, our study reveals that production of new cardiomyocytes and their infiltration into the injured region relies on H3K27me3-mediated sarcomeric and actomyosin cytoskeletal gene repression.

搜集汇总

背景与挑战

背景概述

该数据集是一个RNA-seq研究，聚焦于斑马鱼心脏再生过程中H3K27me3修饰对心肌细胞增殖和再生的调控机制。研究通过比较稳态和再生心肌细胞的转录组变化，发现H3K27me3在肌节和细胞骨架基因启动子上的沉积对心肌细胞胞质分裂和损伤浸润至关重要。数据集包含6个样本，覆盖再生和未损伤心肌细胞，使用Illumina HiSeq 2000平台进行测序，旨在揭示表观遗传修饰在心脏再生中的关键作用。