HOPX-associated molecular programs control cardiomyocyte cell states underpinning cardiac structure and function

Clayton E Friedman¹, Seth W Cheetham², Sumedha Negi¹, Richard J Mills³, Masahito Ogawa⁴, Meredith A Redd¹, Han Sheng Chiu¹, Sophie Shen¹, Yuliangzi Sun¹, Dalia Mizikovsky¹, Romaric Bouveret⁴, Xiaoli Chen¹, Holly K Voges⁵, Scott Paterson¹, Jessica E De Angelis¹, Stacey B Andersen⁶, Yuanzhao Cao¹, Yang Wu¹, Yohaann M A Jafrani², Sohye Yoon⁶, Geoffrey J Faulkner⁷, Kelly A Smith¹, Enzo Porrello⁸, Richard P Harvey⁴, Benjamin M Hogan¹, Quan Nguyen¹, Jian Zeng¹, Kazu Kikuchi⁴, James E Hudson⁹, Nathan J Palpant¹⁰

Affiliations

¹ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
² Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia.
³ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia; School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
⁴ Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; School of Clinical Medicine and School of Biotechnology and Biomolecular Science, UNSW Sydney, Kensington, Sydney, NSW 2052, Australia.
⁵ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia.
⁶ Genome Innovation Hub, The University of Queensland, Brisbane, QLD 4072, Australia.
⁷ Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia; Mater Research Institute, University of Queensland, Woolloongabba, QLD 4102, Australia.
⁸ Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia.
⁹ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia; School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
¹⁰ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: n.palpant@uq.edu.au.

PMID: 38091997
DOI: 10.1016/j.devcel.2023.11.012

Free article

HOPX-associated molecular programs control cardiomyocyte cell states underpinning cardiac structure and function

Clayton E Friedman et al. Dev Cell. 2024.

Free article

. 2024 Jan 8;59(1):91-107.e6.

doi: 10.1016/j.devcel.2023.11.012. Epub 2023 Dec 12.

Authors

Affiliations

¹ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
² Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia.
³ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia; School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
⁴ Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; School of Clinical Medicine and School of Biotechnology and Biomolecular Science, UNSW Sydney, Kensington, Sydney, NSW 2052, Australia.
⁵ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia.
⁶ Genome Innovation Hub, The University of Queensland, Brisbane, QLD 4072, Australia.
⁷ Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia; Mater Research Institute, University of Queensland, Woolloongabba, QLD 4102, Australia.
⁸ Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia.
⁹ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia; School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
¹⁰ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: n.palpant@uq.edu.au.

PMID: 38091997
DOI: 10.1016/j.devcel.2023.11.012

Abstract

Genomic regulation of cardiomyocyte differentiation is central to heart development and function. This study uses genetic loss-of-function human-induced pluripotent stem cell-derived cardiomyocytes to evaluate the genomic regulatory basis of the non-DNA-binding homeodomain protein HOPX. We show that HOPX interacts with and controls cardiac genes and enhancer networks associated with diverse aspects of heart development. Using perturbation studies in vitro, we define how upstream cell growth and proliferation control HOPX transcription to regulate cardiac gene programs. We then use cell, organoid, and zebrafish regeneration models to demonstrate that HOPX-regulated gene programs control cardiomyocyte function in development and disease. Collectively, this study mechanistically links cell signaling pathways as upstream regulators of HOPX transcription to control gene programs underpinning cardiomyocyte identity and function.

Keywords: CRISPRi; DamID; cardiomyocyte physiology; cell proliferation; complex traits; heart development; human-induced pluripotent stem cell; maturation; regeneration; zebrafish cardiac regeneration.

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Conflict of interest statement

Declaration of interests E.P., R.J.M., and J.E.H. are co-inventors on patents relating to cardiac organoid maturation and cardiac therapeutics. J.E.H. is co-inventor on licensed patents for engineered heart muscle. E.P., R.J.M., and J.E.H. are co-founders, scientific advisors, and stockholders in Dynomics. N.J.P. is an inventor on patents relating to stem cells and heart regeneration and is a co-founder and equity holder in Infensa Bioscience.

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HOPX-associated molecular programs control cardiomyocyte cell states underpinning cardiac structure and function

Affiliations

HOPX-associated molecular programs control cardiomyocyte cell states underpinning cardiac structure and function

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

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LinkOut - more resources

Full Text Sources

Molecular Biology Databases