SWI/SNF Component BAF250a Coordinates OCT4 and WNT Signaling Pathway to Control Cardiac Lineage Differentiation.

Ienglam Lei,Yong Zhao,Shuo Tian,Zhong Wang,Victor Chen

doi:10.3389/fcell.2019.00358

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 β-CATENIN during cardiac lineage differentiation from human ESCs. BAF250a deletion greatly reduced the physical interaction between OCT4 and β-CATENIN but did not alter the expression of β-CATENIN and OCT4 in the mesodermal progenitor cells. BAF250a ablation led to decreased recruitment of OCT4 and β-CATENIN at promoters of key mesodermal lineage genes, such as MESP1 and EOMES. Subsequently, the expression of lineage-specific genes was downregulated, whereas the expression of pluripotent genes was upregulated. In parallel, BAF250a ablation also altered recruitments of OCT4 and β-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/β-catenin in mesoderm. In contrast, we found that BAF250a did not regulate the OCT4/β-CATENIN interaction during neuroectoderm differentiation. Altogether, our results suggest that BAF250a specifically controls proper cardiac mesoderm differentiation by reorganizing the binding of OCT4/β-CATENIN and regulates both key lineage differentiation genes and cell cycle genes that coincided in response to WNT/β-CATENIN signal.

Highlights

Dissecting the molecular mechanisms underlying the differentiation of pluripotent stem cells (PSCs) into tissue-specific progenitors and terminal differentiated cell types is key to understanding organ development and regeneration
Deletion of BAF250a at embryonic stem cell (ESC) stage led to decreased differentiation efficiency of cardiac mesoderm (MESP1+) cell and ISL1+ cardiac progenitor cells (CPCs) (Figure 1D) and significant reduction of cTNT+ CMs (Figure 1D). These results indicated that BAF250a was dispensable in the primitive induction during human ESCs (hESCs) differentiation and was required for efficient cardiomyocyte differentiation from mesodermal progenitor cells
To further determine how the disassociation of OCT4/ β-CATENIN contributed to the later cardiac differentiation defects shown in Figure 1, we examined how the cell cycle and genes essential for cell cycle regulation were affected by BAF250a ablation, as cell cycle control is a key regulatory process for differentiation (Ruijtenberg and van den Heuvel, 2015), and BAF250a, OCT4, and WNT/β-CATENIN are all involved in cell cycle regulation

Summary

Introduction

Dissecting the molecular mechanisms underlying the differentiation of pluripotent stem cells (PSCs) into tissue-specific progenitors and terminal differentiated cell types is key to understanding organ development and regeneration. Embryonic cardiac progenitor cells (CPCs) are promising cell sources for cell-based therapies for heart disease. Direct differentiation of CPCs. BAF250a Mediates OCT4/β-CATENIN Interaction in Cardiogenesis from PSCs has been achieved based on the knowledge of embryonic development (Kattman et al, 2011; Lian et al, 2012). Each step of differentiation is tightly regulated by stagespecific signals and epigenetic regulation (Alexander et al, 2015). Epigenetic regulations including histone modification and chromatin remodeling are believed to contribute to the precise of cardiac differentiation (Wamstad et al, 2012). How WNT signaling and epigenetic regulation work together to direct cardiac differentiation is poorly understood

Methods

Results

Conclusion