Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of cardiac development and disease. However, our understanding of the importance of these molecules in cardiac fibrosis is limited. Using an integrated genomic screen, researchers at the University of Lausanne Medical School identified Wisper (Wisp2 super-enhancer-associated RNA) as a cardiac fibroblast-enriched lncRNA that regulates cardiac fibrosis after injury. Wisper expression was correlated with cardiac fibrosis both in a murine model of myocardial infarction (MI) and in heart tissue from human patients suffering from aortic stenosis. Loss-of-function approaches in vitro using modified antisense oligonucleotides (ASOs) demonstrated that Wisper is a specific regulator of cardiac fibroblast proliferation, migration, and survival. Accordingly, ASO-mediated silencing of Wisper in vivo attenuated MI-induced fibrosis and cardiac dysfunction. Functionally, Wisper regulates cardiac fibroblast gene expression programs critical for cell identity, extracellular matrix deposition, proliferation, and survival. In addition, its association with TIA1-related protein allows it to control the expression of a profibrotic form of lysyl hydroxylase 2, implicated in collagen cross-linking and stabilization of the matrix.
(A) Selection strategy of novel SE-associated lncRNAs from a genome-wide profiling of the cardiac transcriptome after MI. (B) Schematic of an intergenic lncRNA located between two PCGs. Heat map showing clustering of heart-enriched intergenic lncRNAs differentially expressed after MI (adjusted P < 0.01). (C) Volcano plot of lncRNAs associated with TEs (triangle) or with SEs (circle). The x axis shows lncRNAs expression in infarcted versus sham-operated animals (log2 fold change) quantified from RNA-seq data; the y axis shows adjusted P value. Wisper expression in sham-operated (black bar) and infarcted heart (red bar) is expressed in FPKM (fragments per kilobase of exon per million fragments mapped). Bars represent mean ± SEM (n = 4). P value was determined by Student’s t test. (D) qRT-PCR analysis of SE-associated lncRNAs (SE-lncRNA) and PCG expression in CMs and fibroblasts isolated from neonatal mouse hearts. Data represent fold change ratio (CM/CF) mean ± SEM (n = 3). P value was determined by Student’s t test. (E) H3K27Ac signature of the locus encompassing Wisper in different human tissues. The red bar highlights the SE region.
Together, these findings identify Wisper as a cardiac fibroblast-enriched super-enhancer-associated lncRNA that represents an attractive therapeutic target to reduce the pathological development of cardiac fibrosis in response to MI and prevent adverse remodeling in the damaged heart.