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, we identified Wisper (Wisp2 super-enhancerassociated 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 Competing interests: S.O. and T.P. filed a patent about therapeutic use of cardiac-enriched lncRNAs including Wisper (patent title: "Diagnostic, prognostic and therapeutic uses of lncRNAs for heart disease and regenerative medicine″; international application number: PCT/EP2014/078868; applicant: University of Lausanne). Data and materials availability:All the data and materials are available through the Gene Expression Omnibus using the following accession numbers: LV (GSM908951 and GSM906396), adipose tissue (GSM906394), adrenal gland (GSM1013126 and GSM896163), bladder (GSM1013133), gastric (GSM1013122, GSM1013128, and GSM910555), ovary (GSM956009), pancreas (GSM1013129 and GSM906397), colon (GSM915331 and GSM910559), small intestine (GSM1013131), spleen (GSM1013132 and GSM906398), and thymus (GSM1013125). HHS Public Access

Enhancers and long noncoding RNAs (lncRNAs) are key determinants of lineage specification during development. Here, we evaluate remodeling of the enhancer landscape and modulation of the lncRNA transcriptome during mesendoderm specification. We sort mesendodermal progenitors from differentiating embryonic stem cells (ESCs) according to Eomes expression, and find that enhancer usage is coordinated with mesendoderm-specific expression of key lineage-determining transcription factors. Many of these enhancers are associated with the expression of lncRNAs. Examination of ESC-specific enhancers interacting in three-dimensional space with mesendoderm-specifying transcription factor loci identifies MesEndoderm Transcriptional Enhancer Organizing Region (Meteor). Genetic and epigenetic manipulation of the Meteor enhancer reveal its indispensable role during mesendoderm specification and subsequent cardiogenic differentiation via transcription-independent and -dependent mechanisms. Interestingly, Meteor-deleted ESCs are epigenetically redirected towards neuroectodermal lineages. Loci, topologically associating a transcribed enhancer and its cognate protein coding gene, appear to represent therefore a class of genomic elements controlling developmental competence in pluripotency.