Baf250a orchestrates an epigenetic pathway to repress the Nkx2.5-directed contractile cardiomyocyte program in the sinoatrial node

Abstract

The sinoatrial node (SAN) is essential for rhythmic beating of the heart; however, our understanding of what controls proper functioning of the SAN remains primitive. To explore molecular control of SAN function, we specifically deleted Baf250a, a key regulatory component of the ATP-dependent chromatin remodeling complex SWI/SNF, in the SAN. Deletion of Baf250a in the SAN led to sinus bradycardia. Time series analysis of dysregulated genes after deletion of Baf250a reveals a transcriptional hierarchy maintaining pacemaker cell identity, i.e., Baf250a activates the expression of Tbx3, and Baf250a, Tbx3 and histone deacetylase 3 coordinately repress the expression of Nkx2.5. Disruption of this repressive pathway switches on expression of Nkx2.5, which stimulates expression of Gata4 and Tbx5. These three cardiac transcription factors further turn on a contractile cardiomyocyte program in the SAN, which eventually leads to sick sinus disease (SSD). Our study suggests that disruption of key genetic pathways regulating cardiac lineage segregation may cause SSD and cardiac arrhythmias in general.

The formation and function of the cardiac conduction system

“…In the SAN, too, Hdac3is involved in Nkx2-5 repression. By direct interaction with Tbx3 and Baf250a (Arid1a), a key component of the SWI/SNF family of chromatin remodelling complex, a dynamic equilibrium of acetylation and deacetylation on the Nkx2-5 promoter leads to transcriptional repression in the SAN (Wu et al, 2014). Conversely, regulatory sequences upstream of Baf250a are co-occupied by Nkx2-5, Shox2 and Tbx5, suggesting a mechanism in which these factors mediate the expression of Baf250a in the SAN (Ye et al, 2015).…”

“…For example, Hdac3, a member of the Class I HDAC family, has been implicated in cardiac development and homeostasis (Montgomery et al, 2008;Singh et al, 2011), acting by repressing the expression of Tbx5 in early development (Lewandowski et al, 2014). During development, it is highly expressed in the SAN (Wu et al, 2014), AVN and Purkinje fibres (Risebro et al, 2012). The prospero-related homeobox protein 1 (Prox1) recruits Hdac3in the AVN and Purkinje fibres to repress Nkx2.5 directly through a proximal upstream enhancer, thereby controlling electrophysiological homeostasis in the adult heart (Risebro et al, 2012).…”

A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

“…This is best exemplified by the co-occupancy of Shox2 and Nkx2-5 on the regulatory elements of Baf250a (Fig. 7E), a key regulatory component of the ATP-dependent chromatin remodeling complex SWI/SNF and a factor proven to be essential for maintaining Hcn4 expression and SAN function (Wu et al, 2014).…”

“…S11), overlap with those of Nkx2-5 and Tbx5. Among these genes, Baf250a (Arid1a) was shown to be essential for maintaining Hcn4 expression and SAN function (Wu et al, 2014), and Cdk6 and Anapc10 are known downstream targets of Tbx5 (Xie et al, 2012), suggesting a co-regulation of these target genes by Shox2, Nkx2-5 and Tbx5 directly. The reported physical interaction between Nkx2-5 and Tbx5 (He et al, 2011;Hiroi et al, 2001) and the evident interaction between Shox2 and Nkx2-5 (Fig.…”

ATP-dependent chromatin remodeling during mammalian development

“…Another BAF subunit, BAF250A, has crucial functions during the commitment of cardiac progenitor cells to beating cardiomyocytes or pacemaker cells (Lei et al, 2012;Wu et al, 2014). In the second heart field, Baf250a (Arid1a) deletion is embryonic lethal at E13, giving rise to a range of structural heart defects.…”