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bioRxiv · 10.1101/524454

SWI/SNF component BAF250a coordinates OCT4 and WNT signaling pathway to control cardiac lineage differentiation

Lei, I.·Tian, S.·Chen, V.·Zhao, Y.·Wang, Z.
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Abstract

Dissecting epigenetic mechanisms controlling early cardiac differentiation will provide insights into heart regeneration and heart disease treatment. SWI/SNF complexes remodel nucleosomes to regulate gene expression and play a key role in organogenesis. Here we reported a unique function of BAF250a in regulating the physical interaction of OCT4 and {beta}-CATENIN during cardiac lineage differentiation from human ESCs. BAF250a deletion greatly reduced the physical interaction between OCT4 and {beta}-CATENIN but did not alter the expression of {beta}-CATENIN and OCT4 in the mesodermal progenitor cells. BAF250a ablation led to decreased recruitment of OCT4 and {beta}-CATENIN at promoters of key mesodermal lineage genes, such as MESP1 and EOMES. Subsequently, the expression of lineage specific genes was down-regulated whereas the expression of pluripotent genes was up-regulated. In parallel, BAF250a ablation also altered recruitments of OCT4 and {beta}-CATENIN to the promoter of CCND2 and CCND3, two key genes for S phase entry during cell cycle. Consequently, BAF250a deletion led to prolonged S phase in Mesp1+ cardiac progenitor cells, which in turn inhibited efficient differentiation of Mesp1+ to Isl1+ cells. Furthermore, BAF250a deletion abolished the interaction of OCT4 and BRG1 in mesoderm, suggesting that BAF250a is the key component in SWI/SNF complex that determines the interaction of Oct4/{beta}-catenin in mesoderm. In contrast, we found that BAF250a did not regulate the OCT4/{beta}-CATENIN interaction during neuroectoderm differentiation. Altogether, our results suggest that BAF250a specifically controls proper cardiac mesoderm differentiation by reorganizing the binding of OCT4/{beta}-CATENIN and regulates both key lineage differentiation genes and cell cycle genes coincided in response to WNT/{beta}-CATENIN signal.\n\nHighlightsBAF250a is required for hESC cardiac differentiation\n\nBAF250a is required for the assembly of Brg1/OCT4/{beta}-CATENIN complex and the recruitment of OCT4/{beta}-CATENIN to cardiac genes\n\nBAF250a is dispensable for the interaction of OCT4/{beta}-CATENIN interaction in neuroectoderm differentiation\n\nBAF250a interacts with OCT4/{beta}-CATENIN to promote cardiac differentiation by regulating cell cycle.

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Lei, I., Tian, S., Chen, V., Zhao, Y., Wang, Z.. 2019-01-18. SWI/SNF component BAF250a coordinates OCT4 and WNT signaling pathway to control cardiac lineage differentiation. https://doi.org/10.1101/524454

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