Specification of the mesodermal lineages requires a complex set of morphogenetic events orchestrated by interconnected signaling pathways and gene regulatory networks. The transcription factor Sox7 has critical functions in differentiation of multiple mesodermal lineages, including cardiac, endothelial, and hematopoietic. Using a doxycycline-inducible mouse embryonic stem cell line, we have previously shown that expression of Sox7 in cardiovascular progenitor cells promotes expansion of endothelial progenitor cells (EPCs). In this study, we show that the ability of Sox7 to promote endothelial cell fate occurs at the expense of the cardiac lineage. Using ChIP-Seq coupled with ATAC-Seq we identify downstream target genes of Sox7 in cardiovascular progenitor cells and by integrating these data with transcriptomic analyses, we define Sox7-dependent gene programs specific to cardiac and EPCs. Furthermore, we demonstrate a protein-protein interaction between SOX7 and GATA4 and provide evidence that SOX7 interferes with the transcriptional activity of GATA4 on cardiac genes. In addition, we show that Sox7 modulates WNT and BMP signaling during cardiovascular differentiation. Our data represent the first genome-wide analysis of Sox7 function and reveal a critical role for Sox7 in regulating signaling pathways that affect cardiovascular progenitor cell differentiation.
Bibliographical noteFunding Information:
This work was supported by NIH/NHLBI (1K08HL102157) to C.M.M. The authors thank Ann Behrens and Kristen Qua-glia for technical assistance. They also thank Dr. Wuming Gong for assistance with the viSNE method to visualize the single-cell qRT-PCR data. They are grateful to the University of Minnesota Genomics Center (UMGC) for sequencing (RNA-Seq, ChIP-Seq and ATAC-Seq) and for the single-cell qRT-PCR analyses.
© 2019, Mary Ann Liebert, Inc.
Copyright 2019 Elsevier B.V., All rights reserved.
- cardiovascular progenitor cells
- transcriptional regulation