Cooperative regulation of Zhx1 and hnRNPA1 drives the cardiac progenitor-specific transcriptional activation during cardiomyocyte differentiation

The zinc finger proteins (ZNFs) mediated transcriptional regulation is critical for cell fate transition. However, it is still unclear how the ZNFs realize their specific regulatory roles in the stage-specific determination of cardiomyocyte differentiation. Here, we reported that the zinc fingers and homeoboxes 1 (Zhx1) protein, transiently expressed during the cell fate transition from mesoderm to cardiac progenitors, was indispensable for the proper cardiomyocyte differentiation of mouse and human embryonic stem cells. Moreover, Zhx1 majorly promoted the specification of cardiac progenitors via interacting with hnRNPA1 and co-activated the transcription of a wide range of genes. In-depth mechanistic studies showed that Zhx1 was bound with hnRNPA1 by the amino acid residues (Thr111-His120) of the second Znf domain, thus participating in the formation of cardiac progenitors. Together, our study highlights the unrevealed interaction of Zhx1/hnRNPA1 for activating gene transcription during cardiac progenitor specification and also provides new evidence for the specificity of cell fate determination in cardiomyocyte differentiation.

Automated summary

The zinc finger proteins (ZNFs) play a critical role in regulating cell fate transition. However, the specific regulatory mechanism of ZNFs in cardiomyocyte differentiation remains unclear. In this study, we found that the transiently expressed Zhx1 protein during cell fate transition from mesoderm to cardiac progenitors is essential for proper cardiomyocyte differentiation in mouse and human embryonic stem cells. Zhx1 interacts with hnRNPA1 to promote the specification of cardiac progenitors and co-activates the transcription of a wide range of genes. Further investigation showed that Zhx1 binds to hnRNPA1 through the amino acid residues (Thr111-His120) of the second Znf domain, contributing to the formation of cardiac progenitors. Our findings provide new insights into the role of Zhx1/hnRNPA1 interaction in gene transcription during cardiac progenitor specification and highlight the specificity of cell fate determination in cardiomyocyte differentiation.