Abstract 14201: Decoding the Genetic Regulation of Cardiac Long Noncoding RNAs in Male and Female Mice Using Integrative Genomic Analysis

Abstract

Introduction: 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 and processing. However, the genetic regulation lncRNAs and their interactions with mRNAs are poorly understood. Hypothesis: Cardiac lncRNAs are genetically regulated and they differentially modulate mRNA expression in female vs male hearts. Methods: Deep RNA-seq was performed using Illumina HiSeqTM 4000 sequencer protocol. SNP Array was used for mouse genotyping. Weighted Gene Co-expression Network Analysis (WGCNA) was conducted using R. Association analyses were performed using FaST-LMM. Results: To elucidate lncRNA-mediated transcriptional regulation in heart, we performed integrated genomic 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. Using a 5% FDR P value threshold, genome-wide quantitative trait locus (eQTL) analysis detected total of 408513 and 404661 locally associated (within 1 Mb of genomic distance of a given gene) SNP-lncRNA pairs in female vs male heart, respectively, which corresponded to 6977 and 6357 unique lncRNAs in female vs male heart, respectively. After excluding those with distal eQTLs ( P <4.1e-6), 2687 and 2684 cardiac lncRNAs with cis eQTLs were retained. WGNCA revealed distinct lncRNA-mRNA modules. From module-trait correlation analysis, 14 female and 5 male modules correlated with heart weight, body fat, or insulin resistance (Bicor >0.3, P <0.05). By applying eQTL analysis to the module eigengenes, 11 modules were identified with eigengenes QTLs (FDR<0.05). Lastly, a novel SNP-lncRNA-mRNA regulatory circuit involving the mitochondria transcription elongation factor, TSFM, was revealed from our analysis. Conclusions: We present our efforts to investigate lncRNA-mediated regulation of gene expression in female vs male mouse heart across 100 different strains. Our results reveal novel associations on lncRNAs with complex clinical traits and provide resources to facilitate mechanistic exploration of lncRNAs contribution to cardiovascular diseases.