Genome-wide studies reveal the essential and opposite roles of ARID1A in controlling human cardiogenesis and neurogenesis from pluripotent stem cells

Xiaona Chu,Yi Sheng,Sheng Liu,Weinian Shou,Jun Wan,Lei Han,Juli Liu,Yunlong Liu,Hongyu Gao,Lei Yang,Yue Wang

doi:10.1186/s13059-020-02082-4

Abstract

BackgroundEarly human heart and brain development simultaneously occur during embryogenesis. Notably, in human newborns, congenital heart defects strongly associate with neurodevelopmental abnormalities, suggesting a common gene or complex underlying both cardiogenesis and neurogenesis. However, due to lack of in vivo studies, the molecular mechanisms that govern both early human heart and brain development remain elusive.ResultsHere, we report ARID1A, a DNA-binding subunit of the SWI/SNF epigenetic complex, controls both neurogenesis and cardiogenesis from human embryonic stem cells (hESCs) through distinct mechanisms. Knockout-of-ARID1A (ARID1A−/−) leads to spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESCs. Additionally, when compared with WT hESCs, cardiac differentiation from ARID1A −/− hESCs is prominently suppressed, whereas neural differentiation is significantly promoted. Whole genome-wide scRNA-seq, ATAC-seq, and ChIP-seq analyses reveal that ARID1A is required to open chromatin accessibility on promoters of essential cardiogenic genes, and temporally associated with key cardiogenic transcriptional factors T and MEF2C during early cardiac development. However, during early neural development, transcription of most essential neurogenic genes is dependent on ARID1A, which can interact with a known neural restrictive silencer factor REST/NRSF.ConclusionsWe uncover the opposite roles by ARID1A to govern both early cardiac and neural development from pluripotent stem cells. Global chromatin accessibility on cardiogenic genes is dependent on ARID1A, whereas transcriptional activity of neurogenic genes is under control by ARID1A, possibly through ARID1A-REST/NRSF interaction.

Highlights

Human cardiogenesis and neurogenesis occur contemporaneously, and both have a similar process of morphogenesis including germ layer segregation, progenitor cell differentiation, cell fate specification, cell migration, left/right patterning, and dorsal/ventral patterning [1,2,3]
Neural crest cells (NCCs), which are capable of differentiation into peripheral neurons and glia, are able to migrate from the pharyngeal arch arteries (PAA) and heart outflow tract (OFT) to the primitive heart and give rise to smooth muscle, connective tissue, and great arteries of the heart [4]
Whole mRNA-seq predicts ARID1A in cardiac development from hESCs Previously, we established a cardiovascular differentiation protocol from human embryonic stem cells by adding different combinations of growth factors including BMP4/bFGF/Activin A and VEGF/DKK1 at different stages [26]

Summary

Introduction

Human cardiogenesis and neurogenesis occur contemporaneously, and both have a similar process of morphogenesis including germ layer segregation, progenitor cell differentiation, cell fate specification, cell migration, left/right patterning, and dorsal/ventral patterning [1,2,3]. Newborns with congenital heart defects exhibited a high frequency of neurodevelopmental deficits [4, 5]. The molecular mechanisms driving both cardiogenesis and neurogenesis in human embryos remain unclear. A better understanding of these mechanisms is critical for studying etiology of human congenital cardiac and neural defects. Human heart and brain development simultaneously occur during embryogenesis. In human newborns, congenital heart defects strongly associate with neurodevelopmental abnormalities, suggesting a common gene or complex underlying both cardiogenesis and neurogenesis. Due to lack of in vivo studies, the molecular mechanisms that govern both early human heart and brain development remain elusive

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