Single-cell multi-modal integrative analyses highlight functional dynamic gene regulatory networks directing human cardiac development

Alyssa R Holman; Shaina Tran; Eugin Destici; Elie N Farah; Ting Li; Aileena C Nelson; Adam J Engler; Neil C Chi

doi:10.1016/j.xgen.2024.100680

Single-cell multi-modal integrative analyses highlight functional dynamic gene regulatory networks directing human cardiac development

Cell Genom. 2024 Nov 13;4(11):100680. doi: 10.1016/j.xgen.2024.100680. Epub 2024 Oct 21.

Authors

Alyssa R Holman¹, Shaina Tran², Eugin Destici², Elie N Farah², Ting Li², Aileena C Nelson³, Adam J Engler⁴, Neil C Chi⁵

Affiliations

¹ Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
² Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
³ Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Institute of Engineering Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
⁵ Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Institute of Engineering Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].

Abstract

Illuminating the precise stepwise genetic programs directing cardiac development provides insights into the mechanisms of congenital heart disease and strategies for cardiac regenerative therapies. Here, we integrate in vitro and in vivo human single-cell multi-omic studies with high-throughput functional genomic screening to reveal dynamic, cardiac-specific gene regulatory networks (GRNs) and transcriptional regulators during human cardiomyocyte development. Interrogating developmental trajectories reconstructed from single-cell data unexpectedly reveal divergent cardiomyocyte lineages with distinct gene programs based on developmental signaling pathways. High-throughput functional genomic screens identify key transcription factors from inferred GRNs that are functionally relevant for cardiomyocyte lineages derived from each pathway. Notably, we discover a critical heat shock transcription factor 1 (HSF1)-mediated cardiometabolic GRN controlling cardiac mitochondrial/metabolic function and cell survival, also observed in fetal human cardiomyocytes. Overall, these multi-modal genomic studies enable the systematic discovery and validation of coordinated GRNs and transcriptional regulators controlling the development of distinct human cardiomyocyte populations.

Keywords: CRISPR-based functional genomics screening; cardiac development; directed differentiation; gene regulatory networks; multi-omics.

MeSH terms

Gene Expression Regulation, Developmental
Gene Regulatory Networks*
Heart / embryology
Heart / physiology
Humans
Myocytes, Cardiac* / cytology
Myocytes, Cardiac* / metabolism
Single-Cell Analysis*
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Transcription Factors