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Abstract MP203: Decoding The Cardiac Regulatory Long Noncoding RNAs In Male And Female Mice Using Integrative Multiomics Analysis

2021; Lippincott Williams & Wilkins; Volume: 129; Issue: Suppl_1 Linguagem: Inglês

10.1161/res.129.suppl_1.mp203

1524-4571

Marlin Touma, Yang Cao, Calvin Pan, Aldons J. Lusis,

Molecular Biology Techniques and Applications

Background: Long non-coding RNAs (lncRNAs) are increasingly recognized as important regulators of mammalian heart development and potential contributors to human cardiovascular diseases by regulating RNA transcription, translation and processing. However, the genetic regulation lncRNAs and their interactions with mRNAs are poorly understood. Methods: Deep RNA sequencing was performed following Illumina HiSeqTM 4000 sequencer protocol. SNP Array was used for mice genotyping. For differential gene expression analysis (DGE), DE Seq was used. Weighted gene co-expression network analysis (WGCNA) was performed using R. FaST-LMM was used for expression quantitative trait locus (eQTL) analysis. Results: To elucidate lncRNA-mediated transcriptional regulation in heart, we performed integrated multiomics analysis of RNA-seq derived transcriptome and SNP genotype data from the hybrid mouse diversity panel (HMDP) of adult male and female mice hearts across 100 strains. We observed significant variability in cardiac lncRNAs expression across the 100 strains. Using a 5% FDR P value threshold, genome-wide eQTL detected total of408513 and 404661 locally associated (within 1 Mb of genomic distance up- or down-stream of a given gene)SNP-lncRNA pairs in female vs male heart, respectively, which corresponded to 2687 unique lncRNAs in female and 2684 unique lncRNAs in males after excluding those with distal eQTLs (at P <4.1e-6). Genome-wide correlation analysis revealed 2794 local and 1233 distal uniquely co-regulated lncRNA-mRNA pairs ( P< 1e-8).Global WGNCA and module-trait correlation analysis identified 14 female and 5 male lncRNA-mRNA networks(Bicor>0.3) that exhibited significant correlation with heart weight, body fat, or insulin resistance. By applying eQTL analysis to the module eigengenes, we identified 11 unique module eigengenes with eQTLs (FDR<0.05). Conclusions: This study represents the first effort to investigate lncRNA-mediated regulation of gene expression in male and female mouse heart across 100 different strains. The results reveal novel associations of lncRNAs with complex clinical traits and provide resources to facilitate mechanistic exploration of the lncRNAs function in cardiovascular disease models.