Atrial Identity Is Determined by a COUP-TFII Regulatory Network

Abstract

SUMMARY Atria and ventricles exhibit distinct molecular profiles that produce structural and functional differences between the two cardiac compartments. However, factors that determine these differences remain largely undefined. Cardiomyocyte-specific COUP-TFII ablation produces ventricularized atria that exhibit ventricle-like action potentials, increased cardiomyocyte size, and development of extensive T-tubules. Changes in atrial characteristics are accompanied by alterations of 2584 genes, in which 81% of them were differentially expressed between atria and ventricles, suggesting that a major function of myocardial COUP-TFII is to determine the atrial identity. Chromatin immunoprecipitation assays using E13.5 atria identified classic atrial-ventricular identity genes Tbx5, Hey2, Irx4, MLC2v, MLC2a and MLC1a, among many other cardiac genes, as potential COUP-TFII direct targets. Collectively, our results reveal that COUP-TFII confers the atrial identity through direct binding and modulating expression of a broad spectrum of genes that have an impact on atrial development and function.

Axial tubule junctions control rapid calcium signaling in atria

“…Importantly, minimal PLN protein levels in mouse atria resulted in a very low PLN/SERCA2 ratio. This is consistent with an earlier study showing that the transcription factor COUP-TFII suppresses PLN transcription in atria (44 ] jSR ) may exert a nonlinear action on the sensitivity of the RyR2 clusters to be triggered (45,46 2+ signaling in AMs, they also lay the foundation for novel and, most important, atria-specific regulatory ECC mechanisms. Given the relevance and functionality of the membrane-protein network detailed above, we propose a signaling super-hub model that is structurally based on unusually large AT and axial couplon dimensions and that may change our perspective on cell-specific control mechanisms of atrial Ca 2+ signaling and contractile regulation.…”

Nkx genes are essential for maintenance of ventricular identity

“…Although our data clearly indicate the plasticity of ventricular characteristics, we have not yet found any evidence in our studies suggesting that a reciprocal flexibility exists in differentiated atrial cells. In this regard, it is fascinating to note the finding that the atria in mice lacking myocardial expression of the atrial transcription factor gene COUP-TFII (Nr2f2 -Mouse Genome Informatics) exhibit ventricular, rather than atrial, features (Wu et al, 2013). Perhaps both the atrial and ventricular gene expression programs require active repression in the reciprocal chamber in order to preserve chamber-specific characteristics; it will be exciting for future work to illuminate the parallels between the mechanisms that reinforce ventricular and atrial identities.…”

“…Characteristic cell morphologies also differ in each chamber; for instance, in the zebrafish heart tube, ventricular cardiomyocytes are cuboidal whereas atrial cardiomyocytes are squamous (Rohr et al, 2008). Only a few regulators of chamber-specific developmental programs have been identified (Bao et al, 1999;Bruneau et al, 2001a;Bruneau et al, 2001b;Koibuchi and Chin, 2007;Wu et al, 2013;Xin et al, 2007); thus, the full roster of genes guiding assignment and maintenance of chamber identity remains elusive.…”

FGF signaling enforces cardiac chamber identity in the developing ventricle

“…These chamberspecific characteristics reflect the distinct molecular traits of atrial and ventricular cardiomyocytes: for example, each chamber expresses particular transcription factors (Bao et al, 1999;Bruneau et al, 2001;Wu et al, 2013;Xin et al, 2007), utilizes specific myosin isoforms (Berdougo et al, 2003;Bisaha and Bader, 1991;Yelon et al, 1999;Yutzey et al, 1994) and possesses discrete ion channel components (Flagg et al, 2008). Despite the wellestablished differences between atria and ventricles, our understanding of the mechanisms that regulate these features remains incomplete.…”

“…In mice, the atrial transcription factor COUP-TFII (Nr2f2 -Mouse Genome Informatics) regulates the atrial gene expression program (Wu et al, 2013). Tissue-specific deletion of COUP-TFII in differentiated myocardium results in ventricularized atria that express ventricular markers and exhibit electrical activity similar to that of ventricular cells.…”