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, Joseph C. Wu

Research output: Contribution to journalArticlepeer-review

124 Scopus citations


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.

Original languageEnglish
Article number4906
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2018
Externally publishedYes


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