Sex-Biased lncRNAs Inversely Correlate With Sex-Opposite Gene Coexpression Networks in Diversity Outbred Mouse Liver

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

“…HTSeq (0.6.1p1) was then used to obtain read counts for exon collapsed regions of RefSeq genes, and featureCounts (1.4.6-p5) was used to obtain read counts for exon collapsed regions of lncRNA genes. A set of 24,197 annotated mouse RefSeq genes (which includes some RefSeq lncRNAs) and a set of 15,558 liver-expressed lncRNA genes (Lodato et al, 2017;Melia and Waxman, 2019) was considered for differential expression analysis. These lncRNAs include intergenic lncRNAs, as well as lncRNAs that are antisense or intragenic with respect to RefSeq genes, and were discovered using a computational pipeline for lncRNA discovery described elsewhere (Melia et al, 2016) based on 186 mouse liver RNA-seq datasets representing 30 different biological conditions.…”

“…Of these, 13,343 were intergenic, 1,966 were antisense, and 249 were intragenic lncRNAs. 44% of the 15,558 liver-expressed lncRNAs are considered novel (Melia and Waxman, 2019). Differential gene expression analysis revealed that a total of 1,735 RefSeq genes and 442 liver-expressed lncRNA genes responded to treatment with WY-14643 at an expression foldchange >2 at FDR<0.05, with 968 RefSeq genes and 245 lncRNA genes upregulated, and 767 RefSeq genes and 197 lncRNA genes downregulated following WY-14643 treatment ( Table S1A and Table S1B).…”

“…Down-regulation of lncRNA lncOb reduces leptin, leading to a leptin responsive form of obesity (Dallner et al, 2019). Other studies found that lncRNAs are regulated during adipocyte differentiation (Yuan et al, 2019a;Yuan et al, 2019b), are expressed in liver in a sex-dependent manner when regulated by growth hormone (Melia et al, 2016;Melia and Waxman, 2019), and can be strongly induced by xenobiotic exposure (Lodato et al, 2017). A compartment-specific transcriptional profiling approach revealed that lncRNA PAXIP1-AS1 regulates pulmonary arterial hypertension by modulating smooth muscle cell function (Jandl et al, 2019).…”

Impact of 3-dimensional genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

“…The health impacts of sex differences in liver include a higher incidence of aggressive liver cancer in males [5], increased susceptibility to autoimmune hepatitis in females [6], and sex differences in metabolism of some pharmaceuticals and environmental chemicals [7]. Transcriptomic and epigenetic sex-bias is best characterized in mouse liver, where ~1,000 genes [8], including many lncRNA genes [9,10] and miRNAs [11], exhibit sex-biased expression that may be regulated by thousands of sex-specific DNase I hypersensitive sites (DHS) [12,13]. This prior work has shown that the majority of sex-biased genes do not have geneproximal sex-biased chromatin marks or DHS, suggesting most epigenetic sex bias occurs at distal elements such as enhancers [12,13].…”

“…The viewpoints in Figure 4 show merged results from 3 biological replicates (n=3 per sex), each library prepared from a separate CD-1 mouse liver (see Methods) and example libraries shown in Figure S5A,B. Figure 4A shows a viewpoint anchored at a female-biased enhancer near the strongly female-biased gene A1bg (F/M expression ratio of 155) as well as 12 female-biased, mono-exonic lncRNAs [10]. In the female samples, robust interactions are observed between the viewpoint enhancer and three regions, indicated by red arrows.…”