Endothelial Brg1 fine-tunes Notch signaling during zebrafish heart regeneration

Chenglu Xiao; Junjie Hou; Fang Wang; Yabing Song; Jiyuan Zheng; Lingfei Luo; Jianbin Wang; Wanqiu Ding; Xiaojun Zhu; Jing-Wei Xiong

doi:10.1038/s41536-023-00293-4

Endothelial Brg1 fine-tunes Notch signaling during zebrafish heart regeneration

NPJ Regen Med. 2023 Apr 7;8(1):21. doi: 10.1038/s41536-023-00293-4.

Authors

Chenglu Xiao^#^{1

2}, Junjie Hou^#¹, Fang Wang³, Yabing Song⁴, Jiyuan Zheng¹, Lingfei Luo⁵, Jianbin Wang⁴, Wanqiu Ding⁶, Xiaojun Zhu⁷, Jing-Wei Xiong⁸

Affiliations

¹ 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.
² National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, 100193, Beijing, China.
³ College of Pharmaceutical Science, Zhejiang University of Technology, 310014, Hangzhou, China.
⁴ School of Life Sciences, Tsinghua University, 100084, Beijing, China.
⁵ Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, 400715, Chongqing, China.
⁶ 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. dingwq@pku.edu.cn.
⁷ 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. zhuxiaojun@pku.edu.cn.
⁸ 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. jingwei_xiong@pku.edu.cn.

^# Contributed equally.

Abstract

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.

Abstract

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