Evolution of CpG island promoter function underlies changes in KChIP2 potassium channel subunit gene expression in mammalian heart

Abstract

Scaling of cardiac electrophysiology with body mass requires large changes in the ventricular action potential duration and heart rate in mammals. These changes in cellular electrophysiological function are produced by systematic and coordinated changes in the expression of multiple ion channel and transporter genes. Expression of one important potassium current, the transient outward current ( I to ), changes significantly during mammalian evolution. Changes in I to expression are determined, in part, by variation in the expression of an obligatory auxiliary subunit encoded by the KChIP2 gene. The KChIP2 gene is expressed in both cardiac myocytes and neurons and transcription in both cell types is initiated from the same CpG island promoter. Species-dependent variation of KChIP2 expression in heart is mediated by the evolution of the cis -regulatory function of this gene. Surprisingly, the major locus of evolutionary change for KChIP2 gene expression in heart lies within the CpG island core promoter. The results demonstrate that CpG island promoters are not simply permissive for gene expression but can also contribute to tissue-selective expression and, as such, can function as an important locus for the evolution of cis -regulatory function. More generally, evolution of the cis -regulatory function of voltage-gated ion channel genes appears to be an effective and efficient way to modify channel expression levels to optimize electrophysiological function.

Comparative analysis using K-mer and K-flank patterns provides evidence for CpG island sequence evolution in mammalian genomes

“…On the other hand, CpG islands could have played a direct role in evolution of warm-blooded vertebrates, perhaps contributing to the gain of placenta, a hallmark of eutherian mammals (13). In support of the latter, a relationship between evolution of CpG island promoter function and gene expression in mammalian heart was recently reported (14). …”

Empirically founded genotype–phenotype maps from mammalian cyclic nucleotide-gated ion channels

“…This is likely to be particularly relevant for sensory systems (Rosati and McKinnon, 2009), as the function of a given protein is directly implicated in transducing the environmental variables into neuronal signals. However, no special difficulty should arise in developing conceptually similar models that take into account the regulation of ion channel expression (Rosenthal and Bezanilla, 2002;Yan et al, 2012).…”

Transmural gradients in ion channel and auxiliary subunit expression

“…The absence of I to in the guinea pig heart has a straightforward explanation, I to gene subunits are expressed at low levels in the hearts of this species compared to other mammals. In particular, Kv4.2 and KChIP2 mRNA are expressed at very low levels in guinea pig ventricles (Rosati et al, 2008; Yan et al, 2012). Oddly, in pig ventricular myocytes, which also have no discernible I to , Kv4.2 and KChIP2 mRNA and Kv4.2 proteins, were found to be expressed at levels comparable with those of rat heart (Schultz et al, 2007).…”

“…Baseline expression of ion channels in heart appears to be predominantly determined at the level of transcription (Abd Allah et al, 2012; Chandler et al, 2009; Gaborit et al, 2007; Marionneau et al, 2005; Rosati and McKinnon, 2004). Consequently, it is likely that cis-regulatory evolution will be a major factor determining tissue specific channel expression levels in the heart and there is experimental evidence to support this hypothesis (Yan et al, 2012). This does not preclude the possibility that virtually any aspect of the channel biosynthesis pathway, intracellular transport and signaling pathway regulation could also evolve to modify channel expression levels.…”

“…Ion channel auxiliary subunits can be important modifiers of all these processes and are obvious targets for regulatory evolution in order to change functional channel expression levels (Yan et al, 2012). Exactly which proteins qualify as bona fide channel auxiliary subunits eludes a simple definition.…”