Abstract
Congenital heart disease (CHD) arises due to errors during the embryonic development of the heart, a highly regulated process involving an interplay between cell-intrinsic transcription factor expression and intercellular signalling mediated by morphogens. Emerging evidence indicates that expression of these protein-coding genes is controlled by a plethora of previously unappreciated non-coding RNAs operating in complex feedback-control circuits. In this review, we consider the contribution of long non-coding RNA (lncRNA) to embryonic cardiovascular development before discussing applications to CHD diagnostics and therapeutics. We discuss the process of lineage restriction during cardiovascular progenitor cell differentiation, as well as the subsequent patterning of the cardiogenic progenitor fields, taking as an example the regulation of NODAL signalling in left-right patterning of the heart. lncRNA are a highly versatile group. Nuclear lncRNA can target specific genomic sequences and recruit chromatin remodelling complexes. Some nuclear lncRNA are transcribed from enhancers and regulate chromatin looping. Cytoplasmic lncRNA act as endogenous competitors for micro RNA, as well as binding and sequestering signalling proteins. We discuss features of lncRNA that limit their study by conventional methodology and suggest solutions to these problems.
Highlights
Congenital heart disease (CHD) is the most common birth defect, occurring in 0.6–0.9% of live births [1,2]
CHD arises from errors during embryonic development of the heart, and a knowledge of gene regulation and patterning during development is central to an understanding of CHD aetiology and diagnosis
We will go on to explore the role of Long non-coding RNA (lncRNA) in patterning of the emerging cardiogenic fields, taking as our example the process of left-right axis specification by the NODAL pathway, disruption of which is linked to many complex forms of CHD [7,8]
Summary
Congenital heart disease (CHD) is the most common birth defect, occurring in 0.6–0.9% of live births [1,2]. Estimates of their prevalence vary, but some studies have suggested that much of the non-coding genome is transcribed at some point during development [4,5] Beyond their lack of a protein-coding function and their being of a size larger than the better characterised micro RNA (miR)—lncRNA are defined as being greater than 200 nucleotides in length—there is little to unify this group. Exciting evidence suggests that lncRNA may regulate epigenetic patterning of the genome to control fate specification. We will go on to explore the role of lncRNA in patterning of the emerging cardiogenic fields, taking as our example the process of left-right axis specification by the NODAL pathway, disruption of which is linked to many complex forms of CHD [7,8]. We will consider some of the problems and challenges involved in lncRNA research, before going on to review studies which have explored the potential of lncRNA as a biomarker for liquid biopsies, as well as possible therapeutic approaches targeting lncRNA
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