Krüppel-like factor 1 is a core cardiomyogenic trigger in zebrafish

Masahito Ogawa; Fan-Suo Geng; David T Humphreys; Esther Kristianto; Delicia Z Sheng; Subhra P Hui; Yuxi Zhang; Kotaro Sugimoto; Maki Nakayama; Dawei Zheng; Daniel Hesselson; Mark P Hodson; Ozren Bogdanovic; Kazu Kikuchi

doi:10.1126/science.abe2762

Krüppel-like factor 1 is a core cardiomyogenic trigger in zebrafish

Science. 2021 Apr 9;372(6538):201-205. doi: 10.1126/science.abe2762.

Authors

Masahito Ogawa^{1

2}, Fan-Suo Geng^{3

4}, David T Humphreys^{4

5}, Esther Kristianto⁶, Delicia Z Sheng¹, Subhra P Hui¹, Yuxi Zhang⁷, Kotaro Sugimoto¹, Maki Nakayama¹, Dawei Zheng¹, Daniel Hesselson^{4

7

8

9}, Mark P Hodson^{6

10}, Ozren Bogdanovic^{3

11}, Kazu Kikuchi^{12

2

4}

Affiliations

¹ Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
² Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
³ Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
⁴ St. Vincent's Clinical School, University of New South Wales Sydney, Kensington, New South Wales, Australia.
⁵ Molecular, Structural, and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
⁶ Freedman Foundation Metabolomics Facility, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
⁷ Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
⁸ Centenary Institute, The University of Sydney, Newtown, New South Wales, Australia.
⁹ Faculty of Medicine and Health, The University of Sydney, Newtown, New South Wales, Australia.
¹⁰ School of Pharmacy, University of Queensland, Woolloongabba, Queensland, Australia.
¹¹ School of Biotechnology and Biomolecular Sciences, University of New South Wales Sydney, Kensington, New South Wales, Australia.
¹² Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia. kikuchi@ncvc.go.jp.

PMID: 33833125
DOI: 10.1126/science.abe2762

Abstract

Cardiac regeneration requires dedifferentiation and proliferation of mature cardiomyocytes, but the mechanisms underlying this plasticity remain unclear. Here, we identify a potent cardiomyogenic role for Krüppel-like factor 1 (Klf1/Eklf), which is induced in adult zebrafish myocardium upon injury. Myocardial inhibition of Klf1 function does not affect heart development, but it severely impairs regeneration. Transient Klf1 activation is sufficient to expand mature myocardium in uninjured hearts. Klf1 directs epigenetic reprogramming of the cardiac transcription factor network, permitting coordinated cardiomyocyte dedifferentiation and proliferation. Myocardial expansion is supported by Klf1-induced rewiring of mitochondrial metabolism from oxidative respiration to anabolic pathways. Our findings establish Klf1 as a core transcriptional regulator of cardiomyocyte renewal in adult zebrafish hearts.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cardiomegaly, Exercise-Induced
Cell Dedifferentiation
Cell Differentiation
Cell Proliferation
Cellular Reprogramming*
Gene Expression Regulation
Gene Regulatory Networks
Glycolysis
Heart / embryology
Heart / physiology*
Heart Ventricles / cytology
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism*
Muscle Development
Myocardium / metabolism
Myocytes, Cardiac / cytology
Myocytes, Cardiac / physiology*
Pentose Phosphate Pathway
Regeneration*
Zebrafish
Zebrafish Proteins / genetics
Zebrafish Proteins / metabolism*

Substances

Kruppel-Like Transcription Factors
Zebrafish Proteins
klf1 protein, zebrafish