Harnessing the Potential of Long Non-coding RNAs to Manage Metabolic Diseases

Bandesh, Khushdeep; Masih, Daisy; Bhattacharyya, Nirjhar; Bharadwaj, Dwaipayan

doi:10.2174/1381612827666210315145254

Cited by 3 publications

(1 citation statement)

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“…The results of the functional analysis demonstrated that a total of 176 lncRNAs were elevated, while 526 lncRNAs were downregulated in human dermal fibroblasts (HCFs) that were stimulated with transforming growth factor-beta (TGF-β). The identified target genes were shown to be associated with several biological processes, including focal adhesion, metabolic pathways, the Hippo signaling system, the PI3K-Akt (Phosphoinositide 3-kinase-Protein Kinase B) signaling pathway, control of actin cytoskeleton, and hypertrophic cardiomyopathy [ 28 , 67 , 68 ]. The novel lncRNAs identified as NONHSAG005537 and NONHSAG017620 were also found to exert inhibitory effects on the proliferation, migration, invasion, and transformation of human cardiac fibroblasts (HCFs).…”

Section: Unraveling the Role Of Lncrnas In Heart Disease Pathogenesismentioning

confidence: 99%

Long Non-Coding RNAs (lncRNAs) in Heart Failure: A Comprehensive Review

Jha,

Thasma Loganathbabu,

Kumaran

et al. 2023

ncRNA

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Heart failure (HF) is a widespread cardiovascular condition that poses significant risks to a wide spectrum of age groups and leads to terminal illness. Although our understanding of the underlying mechanisms of HF has improved, the available treatments still remain inadequate. Recently, long non-coding RNAs (lncRNAs) have emerged as crucial players in cardiac function, showing possibilities as potential targets for HF therapy. These versatile molecules interact with chromatin, proteins, RNA, and DNA, influencing gene regulation. Notable lncRNAs like Fendrr, Trpm3, and Scarb2 have demonstrated therapeutic potential in HF cases. Additionally, utilizing lncRNAs to forecast survival rates in HF patients and distinguish various cardiac remodeling conditions holds great promise, offering significant benefits in managing cardiovascular disease and addressing its far-reaching societal and economic impacts. This underscores the pivotal role of lncRNAs in the context of HF research and treatment.

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Section: Unraveling the Role Of Lncrnas In Heart Disease Pathogenesismentioning

confidence: 99%

Long Non-Coding RNAs (lncRNAs) in Heart Failure: A Comprehensive Review

Jha,

Thasma Loganathbabu,

Kumaran

et al. 2023

ncRNA

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Identification and characterization of the long non-coding RNA NFIA-AS2 as a novel locus for body mass index in American Indians

et al. 2023

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Background Genome-wide association studies have shown that body mass index (BMI), an estimate of obesity, is highly polygenic. Individual variants typically have small effect sizes, making it challenging to identify unique loci in under-represented ethnic groups which lack statistical power due to their small sample size. Yet obesity is a major health disparity and is particularly prevalent in southwestern American Indians. Here, we identify and characterize a new locus for BMI that was detected by analyzing moderate associations with BMI obtained in a population-based sample of southwestern American Indians together with the well-powered GIANT dataset. Methods Genotypes for 10.5 million variants were tested for association with BMI in 5870 American Indians and 2600 variants that showed an association P < 10−3 in the American Indian sample were combined in a meta-analysis with the BMI data reported in GIANT (N = 240,608). The newly identified gene, NFIA-AS2 was functionally characterized, and the impact of its lead associated variant rs1777538 was studied both in-silico and in-vitro. Results Rs1777538 (T/C; C allele frequency = 0.16 in American Indians and 0.04 in GIANT, meta-analysis P = 5.0 × 10−7) exhibited a large effect in American Indians (1 kg/m2 decrease in BMI per copy of C allele). NFIA-AS2 was found to be a nuclear localized long non-coding RNA expressed in tissues pertinent to human obesity. Analysis of this variant in human brown preadipocytes showed that NFIA-AS2 transcripts carrying the C allele had increased RNA degradation compared to the T allele transcripts (half-lives = 9 h, 13 h respectively). During brown adipogenesis, NFIA-AS2 featured a stage-specific regulation of nearby gene expression where rs1777538 demonstrated an allelic difference in regulation in the mature adipocytes (the strongest difference was observed for L1TD1, P = 0.007). Conclusion Our findings support a role for NFIA-AS2 in regulating pathways that impact BMI.

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A novel antisense lncRNA, ARBAG harboring an RNA destabilizing GWAS variant for C-peptide dictates the transcript isoforms of GABRA6 in cerebellum

Bandesh

Pal

Balakrishnan

et al. 2023

Human Molecular Genetics

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Human disease-associated genetic variations often map to long non-coding RNA (lncRNA) genes; however, elucidation of their functional impact is challenging. We previously identified a new genetic variant rs4454083 (A/G) residing in exon of an uncharacterized lncRNA ARBAG that strongly associates with plasma levels of c-peptide, a hormone that regulates insulin bioavailability. On the opposite strand, rs4454083 also corresponds to an intron of a cerebellum-specific GABA receptor subunit gene GABRA6 that mediates strengthening of inhibitory synapses by insulin. Here, we show that alleles of rs4454083 modulate transcript levels of the antisense gene- ARBAG which then controls the expression of the sense gene- GABRA6. Predisposing to low c-peptide, GG (a minor allele genotype across ethnicities) stabilizes ARBAG lncRNA causing higher transcript levels in cerebellum. ARBAG lncRNA abundance leads to cleavage of GABRA6 mRNA at the complementary region resulting in a dysfunctional GABRA6 protein that would not be recruited for synapse strengthening. Together our findings in human cerebellar cell-line and induced Pluripotent Stem Cells (iPSCs) demonstrate biological role of a novel lncRNA in determining the ratio of mRNA isoforms of a protein-coding gene and the ability of an embedded variant in modulating lncRNA stability leading to inter-individual differences in protein expression.

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Harnessing the Potential of Long Non-coding RNAs to Manage Metabolic Diseases

Cited by 3 publications

References 0 publications

Long Non-Coding RNAs (lncRNAs) in Heart Failure: A Comprehensive Review

Long Non-Coding RNAs (lncRNAs) in Heart Failure: A Comprehensive Review

Identification and characterization of the long non-coding RNA NFIA-AS2 as a novel locus for body mass index in American Indians

A novel antisense lncRNA, ARBAG harboring an RNA destabilizing GWAS variant for C-peptide dictates the transcript isoforms of GABRA6 in cerebellum

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