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

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2024-10-16 DOI:10.1016/j.xgen.2024.100680
Alyssa R Holman, Shaina Tran, Eugin Destici, Elie N Farah, Ting Li, Aileena C Nelson, Adam J Engler, Neil C Chi
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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.

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单细胞多模态综合分析凸显了指导人类心脏发育的功能性动态基因调控网络。
阐明指导心脏发育的精确分步遗传程序有助于深入了解先天性心脏病的机制和心脏再生疗法的策略。在这里,我们将体外和体内人类单细胞多组学研究与高通量功能基因组筛选相结合,揭示了人类心肌细胞发育过程中动态的、心脏特异性基因调控网络(GRN)和转录调控因子。根据单细胞数据重建的发育轨迹意外地揭示了基于发育信号通路的不同基因程序的心肌细胞系。高通量功能基因组筛选从推断出的 GRN 中发现了与每种途径衍生的心肌细胞系功能相关的关键转录因子。值得注意的是,我们发现了一个关键的热休克转录因子 1(HSF1)介导的心脏代谢 GRN,它控制着心脏线粒体/代谢功能和细胞存活,这在人类胎儿心肌细胞中也能观察到。总之,这些多模式基因组研究能够系统地发现和验证控制不同人类心肌细胞群发育的协调GRN和转录调节因子。
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