Long non-coding RNAs in aging and aging-associated diseases

From Longevity Wiki

Long noncoding RNAs (lncRNAs) are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein.[1][2] LncRNAs are roughly classified based on their position relative to protein-coding genes: intergenic (between genes), intragenic/intronic (within genes) and antisense.[3] Until recently, these RNAs were disregarded as “junk”, due to their inability to produce functional proteins. But it is now evident that these lncRNAs can assume crucial roles in almost every aspect of biology.[4][5] Most annotated lncRNAs are RNA polymerase II (Pol II) transcribed; hence, they are similar in structure to mRNA and may have cap structures and poly A tails. Unlike protein-coding mRNAs, lncRNAs exhibit functional uniqueness by participating in and modulating the various cellular processes such as, histone modification, DNA methylation, and cellular transcription.[6][7]

Studies have indicated that lncRNAs are involved in epigenetic, transcriptional, post-transcriptional, and translation regulation, as well as post-translational modification.[8][9]

[10] [11]


Long non-coding RNA in aging-related cardiovascular disease

Cardiovascular diseases (CVDs) are currently the main cause of morbidity and mortality. It was found that 145 lncRNAs are differentially expressed in ischemic cardiomyopathy tissues compared with healthy control samples.[12] Thus, overcoming the challenges of determining cardiac-related lncRNAs and their molecular mechanisms may be significantly beneficial to our further investigations in the diagnosis and treatment of CVDs. However, treatment strategies on targeting lncRNA remain difficult to apply to the clinic. [13][14] [15][16][17]

The endothelial cells that line the vessel walls play an important role in the development of atherosclerosis. Non-coding RNA such as long non-coding RNAs are known to play an important role in endothelial function and are implicated in the disease progression. Of 4465 lncRNAs expressed in the human endothelium, 798 lncRNAs are dysregulated in advanced age.[18] Among these differentially expressed lncRNAs, prostate-cancer-associated transcript 14 (PCAT14), which is localized in the nucleus of young endothelial cells, but significantly reduced in aged endothelium. By silencing PCAT14, it was demonstrated that endothelial cell migration and sprouting capacity were reduced, without affecting the endothelial proliferative capacity. Furthermore, silencing of PCAT14 resulted in increased expression of inflammatory genes (e.g., ICAM1 and SELE) and genes relevant to endothelial cell stalk formation (e.g., JAG1 and ESM1), suggesting that PCAT14 may be important in maintaining the healthy status of the endothelium.[19]

Transcribed-Ultra Conserved Regions (T-UCRs)

The ultraconserved regions (UCRs) are genomic elements longer than 200 bp (range: 200-779 bp) that are absolutely conserved among orthologous regions of human, mouse, and rat genomes. These regions also exhibit extremely high levels of conservation in other species, such as fish, chicken, and fugu, strongly suggesting an extreme negative selection of these sequences.[20] More than 80% of UCRs are intergenic or intronic. The genome-wide profiling reveals that most UCRs are transcriptional active; therefore, these regions are also named transcribed UCRs (T-UCRs).[21] Most T-UCRs may be lncRNAs (long noncoding RNAs), defined as RNAs larger than 200 bp, mostly without coding potential. T-UCRs were associated with different hallmarks and showed great potential as biomarkers in many tumor types.[22]

The studies in the literature about the associations between the presence of SNPs in UCRs and the appearance of different disorders revealed at least 37 polymorphism/phenotype associations covering diseases such as: different types of muscular dystrophies; adolescent idiopathic scoliosis; amyotrophic lateral sclerosis; renal diseases; as well as eye-related diseases; and cancer.[23][24] For example, the T-UCR uc.323 deficiency induced cardiac hypertrophy since uc.323 regulate the expression of cardiac hypertrophy-related genes such as CPT1b (Carnitine Palmitoyl transferase 1b).[25]

Roles of long non-coding RNAs in the development of aging-related neurodegenerative diseases

lncRNA participates in multiple aging-related neurological disorders development. Accumulating evidence has implicated lncRNA dysregulation in neurodegenerative disorders,[26] including Alzheimer’s disease, whereby a group of long non-coding RNAs in blood can serve as a specific biomarker of Alzheimer's disease[27][28] Parkinson’s disease,[29][30] and Huntington’s disease (Tan et al., 2021)

Long non-coding RNAs and rheumatoid arthritis

Various lncRNAs have proven potential as biomarkers and targets for diagnosing, prognosis and treating rheumatoid arthritis.[31] 

Accumulating evidence revealed that the regulatory network that includes long non-coding RNAs (lncRNAs)/circular RNAs (circRNAs), micro RNAs (miRNAs), and messenger RNAs (mRNA) plays important roles in regulating the pathological and physiological processes in rheumatoid arthritis. lncRNAs/circRNAs act as the miRNA sponge and competitively bind to miRNA to regulate the expression mRNA in synovial tissue, fibroblast-like synoviocytes (FLS), and peripheral blood mononuclear cells (PBMCs), participate in the regulation of proliferation, apoptosis, invasion, and inflammatory response.[32]

Role of the lncRNA–miRNA–mRNA Axis in Chronic Inflammatory Airway Diseases

[33] Emerging evidence suggests that lncRNAs account for the regulation of macrophage polarization and subsequent effects on respiratory diseases.[34]

The aging-induced lncRNA MIRIAL

Mirial (MicroRNA-cluster 23a~27a~24-2-associated and Induced by Aging Long non-coding RNA) (transcript ID: Gm26532, ENSMUSG00000097296) is a stable, single-exonic lncRNA with a half-life of 3 hours. MIRIAL is an aging-induced lncRNA which acts as a key regulator of endothelial metabolic and cellular function. MIRIAL promotes cell proliferation, migration and basal angiogenic sprouting while decreasing mitochondrial function. It is polyadenylated, strictly localized to the nucleus and associated with chromatin. In endothelial cells, where it exerts regulatory control over metabolism and mitochondrial copy number by activating the FOXO1 signaling pathway. Forkhead Box O1 (FOXO1) plays a pivotal role in repressing MYC signaling and promoting endothelial quiescence. It is assumed that an Alu element[35] within the MIRIAL transcript forms an RNA∙DNA:DNA triplex with a regulatory region of the FOXO1 gene, resulting in its increased expression. Experiments show that loss of Mirial in vivo has an adverse effect on cardiac outcome after acute myocardial infarction. Moreover, Mirial is an important regulator of vascular endothelial growth factor (VEGF)-A-response. Silencing MIRIAL in pro-angiogenic conditions improves angiogenesis by affecting the p53 pathway and mitochondrial respiration through FOXO1 signaling. Transcriptional modulation of MIRIAL, particularly in the elderly, might be a good strategy to improve therapeutic angiogenesis.[36]

References

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  2. ↑ Djebali, S., Davis, C. A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., ... & Gingeras, T. R. (2012). Landscape of transcription in human cells. Nature, 489(7414), 101-108. PMID: 22955620 PMC3684276 DOI: 10.1038/nature11233
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  19. ↑ Drekolia, M. K., Talyan, S., Cordellini Emidia, R., Boon, R. A., Guenther, S., Looso, M., ... & Bibli, S. I. (2022). Unravelling the impact of aging on the human endothelial lncRNA transcriptome. bioRxiv, 2022-09. PMID: 36338971 PMCID: PMC9634578 DOI: 10.3389/fgene.2022.1035380
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  36. ↑ Kohnle, C., Koziarek, S., Warwick, T., Theodorou, K., Fischer, A., Juni, R. P., ... & Boon, R. A. (2024). The aging-induced long non-coding RNA MIRIAL controls endothelial cell and mitochondrial function. bioRxiv, 2024-02. https://doi.org/10.1101/2024.02.28.582649

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