Novel Transcriptomic Interactomes of Noncoding RNAs in the Heart under Altered Thyroid Hormonal States

Abstract

Noncoding RNAs are emerging as vital players in cardiovascular diseases. Thyroid hormones (THs) are crucial for cardiovascular survival; however, correction of systemic hypothyroidism (low serum THs) may not improve cardiac tissue-level hypothyroidism or cardiac function. Mechanistically, the understanding of noncoding transcriptomic interactions influencing TH-mediated cardiac effects is unclear. Adult C57BL/6J mixed-sex mice were randomized into Control, Hypothyroid (HypoTH), Hyperthyroid (HyperTH), and HypoTH-Triiodothyronine restoration groups. Physiological, morphological, biochemical, molecular, and whole transcriptomic studies and appropriate statistical analyses were performed. HypoTH showed significant atrophy, depressed cardiac function, and decreased serum THs versus controls, and Triiodothyronine supplementation restored them. HyperTH significantly increased serum THs with hypertrophy. Real-time PCR showed significantly altered inflammatory and immune lncRNAs. The transcriptomic sequencing revealed significant differential expressions of lncRNAs, miRNAs, and mRNAs. Eleven novel circRNAs significantly decreased with increased THs. Multiple pathways were GO-/KEGG-enriched, including cardiac, thyroid, cancer, mitochondrial, inflammatory, adrenergic, metabolic, immune-mediated, vesicular, etc. We also uncovered significant novel co-expression and interactions of lncRNA-miRNA, lncRNA-miRNA-mRNA, lncRNA-mRNA, circRNA-miRNA, and miRNA-mRNA, and splicing events. This includes a novel pathway by which the predominant cardiac TH receptor alpha may interact with specific lncRNAs and miRNAs. This is the first study reporting a comprehensive transcriptome-wide interactome in the cardiac–thyroid axis.

Noncoding RNAs and Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Cardiac Arrhythmic Brugada Syndrome

“…Several of the identified genes have been shown to be mediated by ncRNAs. More such findings can help develop a comprehensive transcriptomic network of how coding and ncRNAs interact to coordinately influence the genotype and phenotype of BrS [82]. The prospective BrAID multicenter clinical study involving the integration of machine learning algorithms and transcriptomics is expected to shed new light on mechanisms of type 1 BrS [190].…”

“…Only about 2% of the entire human genome (<5% of the mammalian genome) is protein-coding. Nonetheless, a large majority of the remainder of the genome (noncoding) is actively transcribed/transcribable [80][81][82]. Genome-wide association studies (GWAS) have also shown that most of the loci associated with electrophysiological traits are located in noncoding regulatory regions and are expected to affect gene expression dosage and cardiac ion channel function [74,83].…”

“…In contrast to the short noncoding miRNAs, long noncoding RNAs (lncRNAs), as their name implies, are significantly lengthier molecules with >200 nucleotides [82]. LncRNAs are the largest population of ncRNAs, and human lncRNA genes exceed protein-coding genes by about 4.8-fold [101].…”

“…Although lncRNA sequences are not as conserved as miRNAs across species, studies indicate conservation of lncRNA structure and function [106,107]. LncR-NAs may be either linear (more widely studied) or circular (circRNAs), and both play important roles in CV disorders [82,88,108,109].…”