Long Noncoding RNAs in Cardiac Development and Pathophysiology

Abstract

Heart function requires sophisticated regulatory networks to orchestrate organ development, physiological responses, and environmental adaptation. Until recently, it was thought that these regulatory networks are composed solely of protein-mediated transcriptional control and signaling systems; consequently, it was thought that cardiac disease involves perturbation of these systems. However, it is becoming evident that RNA, long considered to function primarily as the platform for protein production, may in fact play a major role in most, if not all, aspects of gene regulation, especially the epigenetic processes that underpin organogenesis. These include not only wellvalidated classes of regulatory RNAs, such as microRNAs, but also tens of thousands of long noncoding RNAs that are differentially expressed across the entire genome of humans and other animals. Here, we review this emerging landscape, summarizing what is known about their functions and their role in cardiac biology, and provide a toolkit to assist in exploring this previously hidden layer of gene regulation that may underpin heart adaptation and complex heart diseases. (Circ Res. 2012;111:1349-1362.)

Genetic Networks Governing Heart Development

“…The Bvht gene produces a 590-nucleotide transcript spliced from three exons. No homologs have been identified in human or rat, consistent with the higher divergence of ncRNAs that are unconstrained by the requirement for codon structure and function (Schonrock et al 2012). shRNA knockdown of Bvht in ESCs appeared to specifically affect the cardiovascular lineages, and lead to down-regulation of kernel TF genes, such as Hand1, Hand2, Nkx2-5, and Tbx20.…”

“…Recent findings indicate that 80% of the human genome is either transcribed or associated with other chromatin regulatory events, far greater than the 3% representing protein-coding exons. Thus, a large proportion of the genome has a regulatory role including specification of long ncRNAs, the functions of which we are only beginning to grasp (Schonrock et al 2012) (see below). There is also a greater diversity of transcript structure owing to differential splicing than previously appreciated, and many genes utilize alternative transcriptional start sites.…”

“…Others may act as scaffolds for chromosomal organization or as miRNA sponges, and many other functions have been described (Morris and Mattick 2014). The analysis of lncRNA function in the heart is only beginning, and this area has been recently reviewed (Schonrock et al 2012;Peters and Schroen 2014) along with genome tools that facilitate research into the area (Schonrock et al 2012). New tools, such as ChIRP (chromatin isolation by RNA purification), in which individual ncRNAs are captured using biotinylated oligonucleotides, are enabling genomic occupancy and bound protein and RNA components to be identified at high resolution (Chu et al 2011).…”

Interplay of chromatin modifications and non-coding RNAs in the heart

“…Recent experimental observations show that chromatin remodeling and histone modification confer important transcriptional programs as a result of development and cardiac disease. [12][13][14][15] The diverse interplay of histone modifying enzymes interacting with long non-coding RNAs (lncRNA) that serve to localize DNA-binding proteins as well as direct specific post-translational modifications to regulate gene expression has been described and is the focus of our discussion.…”

A bioinformatics method for predicting long noncoding RNAs associated with vascular disease

“…Historically, people often argue against the functionality of lncRNAs [3] because they normally tend to show low cross-species conservation, low expression levels and high tissue specificity. Recently, however, increasing evidence has suggested that a number of lncRNAs have important and diverse functions [4]. Therefore, it will be no surprise the dysfunction of lncRNAs is associated with a wide spectrum of disease, including cardiovascular disease [5] and cancer [6].…”