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

Abstract

Background: Early 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. Results: Here, 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. Conclusions: We 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.

The SMC5/6 complex compacts and silences unintegrated HIV-1 DNA and is antagonized by Vpr

“…Vpr therefore releases unintegrated viral DNA from the chromatin compaction imposed by the SMC5/6 complex. The 1.9-fold increase in ATAC-seq read counts upon SLF2 depletion is of similar magnitude to changes reported on chromatin accessibility following depletion of chromatin remodelers, such as the SWI/SNF complex component ARID1A (Liu et al, 2020). These changes are therefore consistent with a functionally relevant effect on silencing.…”

The Evolutionary Conserved SWI/SNF Subunits ARID1A and ARID1B Are Key Modulators of Pluripotency and Cell-Fate Determination

“…Similar results were published by Liu J. et al (2020) , who investigated the role of ARID1A in early human cardiac development and neurogenesis. The study demonstrated that homozygous deletion of ARID1A in human ESCs results in spontaneous neuronal differentiation due to increased expression of several genes associated with neurodevelopment.…”

“…The study demonstrated that homozygous deletion of ARID1A in human ESCs results in spontaneous neuronal differentiation due to increased expression of several genes associated with neurodevelopment. Simultaneously, the same cells displayed downregulation of genes associated with cardiomyocyte differentiation ( Liu J. et al, 2020 ).…”

Autism-associated protein POGZ maintains embryonic stem cells by association with esBAF and HP1γ

“…BRG1 is required for ESC self-renewal and pluripotency, by modulating chromatin accessibility at key regulatory elements (Kidder et al, 2009; King and Klose, 2019; Lei et al, 2015). Disruption of other esBAF core subunits, such as BAF60a, BAF250a and BAF155, also results in disruption of ESC self-renewal and pluripotency defects (Alajem et al, 2015; Gao et al, 2008; Gao et al, 2019; Ho et al, 2008; Liu et al, 2020; Schaniel et al, 2009; Takebayashi et al, 2013; Zhang et al, 2014).…”

“…The role of esBAF complex in the maintenance of ESCs has been firmly established. Disruption of esBAF core subunits, such as BRG1, BAF60a, BAF250a and BAF155, results in ESC self-renewal and pluripotency defects (Alajem et al, 2015; Gao et al, 2008; Gao et al, 2019; Ho et al, 2008; Kidder et al, 2009; King and Klose, 2019; Lei et al, 2015; Liu et al, 2020; Schaniel et al, 2009; Takebayashi et al, 2013; Zhang et al, 2014).…”