Novel Targets Emerging From Human Genome and Epigenome Research
An increasing spectrum of endogenous ncRNAs is employed for the development of novel therapeutic ncRNA tools optimized for specific therapeutic requirements.[88,243–248] ncRNAs are not only employed as tools, but the exploration of the non-coding human genome has also greatly expanded the spectrum of possible therapeutic targets. Figure 7 puts the number of protein-coding genes into relation with the largely unexplored universe of non-coding (regulatory, architectural) transcripts including microRNAs (miRs), lncRNAS, circRNAs, and others.[57–62,67,74,249–286]
Novel therapeutic targets emerging from recent genome and epigenome research. Beyond classical protein targets (e.g. enzymes, receptors), a very broad spectrum of novel non-protein targets has emerged from recent human genome and epigenome research. The ENCODE Project has revealed that >98% of the human genome do not encode proteins, but a plethora of RNA species ranging in size from small RNAs (miRNAs, siRNAs, piRNAs, tRNA-like RNAs) to very large transcripts (lncRNAs) many of which undergo complex transcriptional processing giving rise to multiple types of offspring. In effect, the number of now recognized possible RNA-type targets for pharmacotherapy has increased by ≈two orders of magnitude since the finalization of the Human Genome Project. In parallel with this development, multiple tools for RNA-type target modulation have emerged (ASOs, siRNAs, CRISPR) which in the future may enable an increasing number of novel molecular therapeutic strategies.
There is growing evidence that multiple non-coding genomic regions are not single-function units comparable to classical protein-coding genes, but that they instead are highly integrated RNA processing systems which control complex biological programmes, e.g. cell proliferation and migration at the cellular level. Beyond that, they may co-ordinate complex systems level biological processes, e.g. the innate and acquired immune response. Optimal control of these systems is lost in multiple CVDs and their restoration may have critical impact on disease progression or healing. Recent research suggests the existence of 'master regulators' at the epigenome and non-coding genome level, and these may constitute useful and truly novel therapeutic targets.
One 'high-level' co-ordinator of this type is illustrated in Figure 8 which summarizes recent work demonstrating critical influence of lncRNA NEAT1 upon stem cell differentiation and immune functions, respectively. NEAT1 is also overexpressed in Parkinson's disease substantia nigra and confers drug-inducible neuroprotection from oxidative stress. Knockdown of NEAT1 induces tolerogenic phenotype in dendritic cells by inhibiting activation of NLRP3 inflammasome.
Integration of cellular subsystems into complex biological programmes. Extended regions of the non-coding genome and epigenome appear to have evolved to co-ordinate the complex systemic response of higher organism to environmental challenges. Thus, an appropriate immune response needs to provide proper activation of multiple interacting immune cell types to ensure efficient control/repair of an infection/tissue injury. Furthermore, there need to exist genome/epigenome-encrypted programmes to enable downregulation of all immune system components to baseline, once the infection is overcome or the tissue injury repaired. Recent research suggests that such regions could possibly be amenable to novel molecular approaches targeting RNAs (eg architectural lncRNAs) or epigenetic regulators (e.g. chromatin remodelling complexes).
Eur Heart J. 2020;41(40):3884-3899. © 2020 Oxford University Press
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