MicroRNAs Telltale Effects on Signaling Networks in Cardiomyopathy

Abstract

MicroRNAs (miRNAs) are single-stranded, highly conserved, short non-coding RNAs (~ 22 nucleotides) regulating target gene expression by base pairing with specific sequences of target mRNAs (Ambros, 2004). miRNAs negatively regulate gene expression posttranscriptionally by suppressing translation and/or inducing mRNA degradation. Bioinfomatically, it is estimated that human genome may contain approximately 1000 miRNAs (Bartel, 2004; Berezikov et al., 2005; Griffiths-Jones et al., 2008) and consistently, additional miRNAs are continually being identified (Griffiths-Jones et al., 2006). miRNAs modulate the expression of target proteins in a non-canonical manner by binding to specific sequences regulating functional networks. Consequentially, a single miRNA might target hundreds of distinct genes or alternatively expression of a single coding gene can be regulated by many different miRNAs (Lewis et al., 2005; Miranda et al., 2006). Recent studies show the important role of miRNAs in the regulation of a variety of physiological functions ranging from stem cell differentiation to cardiac muscle development and stress (Krichevsky et al. 2006; Chen et al., 2006; Zhao et al., 2005; Pedersen et al., 2007; Kloosterman et al., 2007; Felli et al., 2005; Tay et al., 2008). Furthermore, aberrant expression of miRNAs has been found in various diseases including cancer, diabetes and cardiac hypertrophy/failure. The binding specificity of miRNAs depend on complementary base pairing of ~ 7 nucleotide seed sequence region at the 5’ end of the miRNA with the corresponding mRNA target. Another caveat that needs to be considered in the miRNA regulation is the miRNA sequences outside the 7 nucleotide seed region which pairs with the mRNA that may also play a role in determining the strength/efficacy of regulating the target mRNA. The binding of miRNAs to their cognate target mRNAs commonly results in decreased expression of target genes through translational repression or mRNA degradation (Fig. 1). Conversely, decreased expression of miRNAs will lead to increased target gene expression (Gregory et al., 2008). This realm of knowledge has allowed for studies on miRNAs on their tissue specificity and disease specificity but critically little information is available with regards to temporal or