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Researchers have revealed how long sections of RNA that do not encode proteins can nonetheless impact on tissue function through their spatial position on chromosomes, which could have applications in targeting disease.

Protein-coding genes account for less than two percent of the human genome and a large proportion of genetic material lacks significant translational potential.

Long, intergenic non-coding (linc)RNA—which are ribonucleic acids longer than 200 nucleotides—are part of this and increasing evidence suggests they play a key role in gene regulation.

LincRNA transcripts are able to have an impact directly by themselves, unlike mRNA which requires translation into proteins to exert its genetic functions.

They can affect chromatin function, signaling pathways, cytoplasmic RNA and the function of membraneless nuclear bodies depending on their localization and interactions with DNA, RNA and protein.

The current study showed that lincRNA loci were spatially concentrated in particular areas of the 3D genomic structure called topological associating domains (TADs).

LincRNAs were more likely to be located within internal TAD areas whereas protein-coding genes were more likely to be found at TAD boundaries, according to the findings published in iScience.

Specifically, lincRNAs derived from TADs appeared to act as markers of the specific tissue they were within, suggesting that TADs could be the basis for tissue-specific expression of lincRNAs.

The findings suggest that lincRNAs could therefore help identify if something goes awry in particular tissues, potentially clarifying the mechanisms by which disease occurs and providing new targets for drug discovery.

“As a dream, if such mechanisms and drug targets could be stratified for individuals based on the lincRNAs regulated by the chromosomal DNA structures like TADs (they could be different across persons), we would be able to directly propose a more practical framework for precision medicine,” said senior researcher  Tatsuhiko Tsunoda, PhD, a medical science mathematics professor at the University of Tokyo.

“By observing the states and the behaviors of TADs and lincRNAs by person, we could be able to apply most appropriate therapies for each patient,” he told Inside Precision Medicine.

Based on their findings, the researchers proposed an analytical framework to interpret transcriptional status using lincRNA as an indicator, which they applied to data on hypertrophic cardiomyopathy (HCM).

This identified genes associated with variations in the specific expression lincRNAs and their upstream genes, which provided insights into the pathways of HCM pathogenesis.

The authors note that, while HCM is often caused by mutations in sarcomere-related genes, there are many cases in which genetic abnormalities are not identified.

There is therefore a need to understand the molecular mechanisms of the pathogenesis of HCM and to develop therapeutic methods.

“Here, based on our new approach and data from patients with multiple genetic backgrounds, we found elevated keratin gene expression and an HCM-specific transcriptional pathway by E2F1 with down-regulation of LINC00881,” the researchers report.

They conclude: “This study will contribute to a fundamental understanding of the molecular basis underlying tissue-/disease-specific expression of lincRNAs.”

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