Loss of the Long Non-coding RNA OIP5-AS1 Exacerbates Heart Failure in a Sex-Specific Manner

Abstract

BackgroundLong ncRNAs (lncRNAs) are known to influence numerous biological processes including cellular differentiation and tissue development. They are also implicated in the maintenance, health and physiological function of many tissues including the heart. Indeed, manipulating the expression of specific lncRNAs has been shown to improve pathological cardiac phenotypes such as heart failure. One lncRNA studied in various settings is OIP5-AS1 (also known as 1700020I14Rik and Cyrano), however its role in cardiac pathologies remains mostly uncharacterised.MethodsWe used data generated from FACS sorted murine cardiomyocytes, human iPSC derived cardiomyocytes, as well as heart tissue from various animal models to investigate OIP5-AS1 expression in health and disease. Using CRISPR we engineered a global OIP5-AS1 knock out (KO) mouse model and performed cardiac pressure overload experiments to study heart failure in these animals. RNA-sequencing of left ventricles provided mechanistic insight between WT and KO mice.ResultsWe demonstrate that OIP5-AS1 expression is regulated during cardiac development and cardiac specific pathologies in both rodent and human models. Moreover, we demonstrate that global female OIP5-AS1 KO mice develop exacerbated heart failure, but male mice do not. Transcriptomics and gene set enrichment analysis suggests that OIP5-AS1 may regulate pathways that impact mitochondrial function.ConclusionsOIP5-AS1 is regulated in cardiac tissue and its deletion leads to worsening heart function under pressure overload in female mice. This may be due to impairments in mitochondrial function, highlighting OIP5-AS1 as a gene of interest in sex-specific differences in heart failure.

Long non‐coding RNA OIP5‐AS1 (Cyrano): A context‐specific regulator of normal and disease processes

“…Future contextual work modulating OIP5‐AS1 in animal models will provide insight into which contexts its dysregulation is a driver of the particular condition, or which are cases of guilt‐by‐association. Intriguingly, studies to date have shown no overt knockout phenotypes in mouse models, 4,132 but instead have revealed elegant roles in specific contexts in the heart and brain, for example, 4,109 suggesting that mechanistic and contextual studies are still needed to fully understand the extent of OIP5‐AS1's functional pleiotropism.…”

“…Stimulated by observations of its enrichment in striated muscle and differentiated cardiomyocytes along with reduced expression in the context of heart failure, a recent study examined roles for OIP5‐AS1 using a model of pressure‐overload induced heart failure (Figure 4). 109 CRISPR/Cas9 was used to generate knockout mouse models, which revealed a sex‐specific role for OIP5‐AS1, wherein female mice were more prone to heart failure than male mice 109 . Authors indicated that this sex‐specific difference was tied to changes in cardiomyocyte metabolism in female knockout mice versus scarring and fibrosis, and were also independent of changes in previously identified OIP5‐AS1 modulators such as miR‐7, miR‐29 or HuR 109 .…”

“… 109 CRISPR/Cas9 was used to generate knockout mouse models, which revealed a sex‐specific role for OIP5‐AS1, wherein female mice were more prone to heart failure than male mice 109 . Authors indicated that this sex‐specific difference was tied to changes in cardiomyocyte metabolism in female knockout mice versus scarring and fibrosis, and were also independent of changes in previously identified OIP5‐AS1 modulators such as miR‐7, miR‐29 or HuR 109 . This cardiac‐health‐related sexual dimorphism has implications in the clinic since there are gender‐related differences in cardiovascular disease for men and women 110 …”

Of mice and human-specific long noncoding RNAs

“…The absence of well-annotated functional motifs in most LncRNAs renders CRISPR targeting of this class of genes in the mouse challenging, though not insurmountable (Miano et al 2019 ). Indeed, several LncRNAs have been targeted with CRISPR in rodents through large deletions of multiple exons or the entire LncRNA locus (Han et al 2014 ; Zhou et al 2021b ; Zhuang et al 2021 ). The approach of removing such large sequences runs the risk of deleting regulatory elements or small intronic RNAs that may compromise accurate interpretation of phenotypes.…”