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Cardiac progenitor formation is one of the earliest committed steps of human cardiogenesis and requires the cooperation of multiple gene sets governed by developmental signaling cascades. To determine the key regulators for cardiac progenitor formation, we have developed a two‐stage genome‐wide CRISPR‐knockout screen. We mimicked the progenitor formation process by differentiating human pluripotent stem cells (hPSCs) into cardiomyocytes, monitored by two distinct stage markers of early cardiac mesodermal formation and commitment to a multipotent heart progenitor cell fate: MESP1 and ISL1, respectively. From the screen output, we compiled a list of 15 candidate genes. After validating seven of them, we identified  ZIC2  as an essential gene for cardiac progenitor formation. ZIC2 is known as a master regulator of neurogenesis. hPSCs with  ZIC2  mutated still express pluripotency markers. However, their ability to differentiate into cardiomyocytes was greatly attenuated. RNA‐Seq profiling of the  ZIC2 ‐mutant cells revealed that the mutants switched their cell fate alternatively to the noncardiac cell lineage. Further, single cell RNA‐seq analysis showed the ZIC2 mutants affected the apelin receptor‐related signaling pathway during mesoderm formation. Our results provide a new link between  ZIC2  and human cardiogenesis and document the potential power of a genome‐wide unbiased CRISPR‐knockout screen to identify the key steps in human mesoderm precursor cell‐ and heart progenitor cell‐fate determination during in vitro hPSC cardiogenesis.

Genome‐wide CRISPR screen identifies ZIC2 as an essential gene that controls the cell fate of early mesodermal precursors to human heart progenitors