Defining human cardiac transcription factor hierarchies using integrated single-cell heterogeneity analysis

Jared M. Churko (), Priyanka Garg, Barbara Treutlein, Meenakshi Venkatasubramanian, Haodi Wu, Jaecheol Lee, Quinton N. Wessells, Shih-Yu Chen, Wen-Yi Chen, Kashish Chetal, Gary Mantalas, Norma Neff, Eric Jabart, Arun Sharma, Garry P. Nolan, Nathan Salomonis () and Joseph C. Wu ()
Additional contact information
Jared M. Churko: Stanford University
Priyanka Garg: Stanford University
Barbara Treutlein: Stanford University
Meenakshi Venkatasubramanian: Cincinnati Children’s Hospital Medical Center
Haodi Wu: Stanford University
Jaecheol Lee: Stanford University
Quinton N. Wessells: Stanford University
Shih-Yu Chen: Stanford University School of Medicine
Wen-Yi Chen: Stanford University
Kashish Chetal: Cincinnati Children’s Hospital Medical Center
Gary Mantalas: Stanford University
Norma Neff: Stanford University
Eric Jabart: Zephyrus Biosciences
Arun Sharma: Stanford University
Garry P. Nolan: Stanford University School of Medicine
Nathan Salomonis: Cincinnati Children’s Hospital Medical Center
Joseph C. Wu: Stanford University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by their immaturity and heterogeneity. To characterize the source of this heterogeneity, we applied complementary single-cell RNA-seq and bulk RNA-seq technologies over time during hiPSC cardiac differentiation and in the adult heart. Using integrated transcriptomic and splicing analysis, more than half a dozen distinct single-cell populations were observed, several of which were coincident at a single time-point, day 30 of differentiation. To dissect the role of distinct cardiac transcriptional regulators associated with each cell population, we systematically tested the effect of a gain or loss of three transcription factors (NR2F2, TBX5, and HEY2), using CRISPR genome editing and ChIP-seq, in conjunction with patch clamp, calcium imaging, and CyTOF analysis. These targets, data, and integrative genomics analysis methods provide a powerful platform for understanding in vitro cellular heterogeneity.

Date: 2018
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DOI: 10.1038/s41467-018-07333-4

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