Xiao Chenglu, Hou Junjie, Wang Fang, Song Yabing, Zheng Jiyuan, Luo Lingfei, Wang Jianbin, Ding Wanqiu, Zhu Xiaojun, Xiong Jing-Wei
Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, 100871, Beijing, China.
National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, 100193, Beijing, China.
NPJ Regen Med. 2023 Apr 7;8(1):21. doi: 10.1038/s41536-023-00293-4.
Myocardial Brg1 is essential for heart regeneration in zebrafish, but it remains unknown whether and how endothelial Brg1 plays a role in heart regeneration. Here, we found that both brg1 mRNA and protein were induced in cardiac endothelial cells after ventricular resection and endothelium-specific overexpression of dominant-negative Xenopus Brg1 (dn-xbrg1) inhibited myocardial proliferation and heart regeneration and increased cardiac fibrosis. RNA-seq and ChIP-seq analysis revealed that endothelium-specific overexpression of dn-xbrg1 changed the levels of H3K4me3 modifications in the promoter regions of the zebrafish genome and induced abnormal activation of Notch family genes upon injury. Mechanistically, Brg1 interacted with lysine demethylase 7aa (Kdm7aa) to fine-tune the level of H3K4me3 within the promoter regions of Notch family genes and thus regulated notch gene transcription. Together, this work demonstrates that the Brg1-Kdm7aa-Notch axis in cardiac endothelial cells, including the endocardium, regulates myocardial proliferation and regeneration via modulating the H3K4me3 of the notch promoters in zebrafish.
心肌中的Brg1对斑马鱼的心脏再生至关重要，但内皮细胞中的Brg1是否以及如何在心脏再生中发挥作用仍不清楚。在这里，我们发现心室切除术后心脏内皮细胞中brg1 mRNA和蛋白均被诱导，并且内皮细胞特异性过表达显性负性非洲爪蟾Brg1（dn-xbrg1）会抑制心肌增殖和心脏再生，并增加心脏纤维化。RNA测序和染色质免疫沉淀测序分析表明，dn-xbrg1的内皮细胞特异性过表达改变了斑马鱼基因组启动子区域中H3K4me3修饰的水平，并在损伤时诱导Notch家族基因的异常激活。从机制上讲，Brg1与赖氨酸去甲基化酶7aa（Kdm7aa）相互作用，以微调Notch家族基因启动子区域内的H3K4me3水平，从而调节Notch基因转录。总之，这项工作表明，心脏内皮细胞（包括心内膜）中的Brg1-Kdm7aa-Notch轴通过调节斑马鱼Notch启动子的H3K4me3来调节心肌增殖和再生。
