Dear Editor, Next-generation sequencing revealed that the majority of the human genome is transcribed but has no coding function. It is estimated that. 30000 long noncoding RNAs (lncRNAs) are expressed in humans, but their functions are largely unknown (Suckau et al., 2009; Rinn and Chang, 2012; Poller et al., 2013). Consideration of noncoding genomic elements in pathogenetic studies is warranted and enabled by technological advances allowing comprehensive transcriptome mapping of protein-coding genes as well as small and long ncRNAs. We searched for lncRNAs influencing antiviral capacity in patients with Coxsackievirus B3 (CVB3) cardiomyopathy (Kuhl et al., 2012) and assign here immunoregulatory functions to the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) anditsenzymaticprocessingproductMALAT1-associated small cytoplasmic RNA (mascRNA). Some lncRNAs undergo complex posttranscriptional processing (Wilusz et al., 2008; Kuhn et al., 2015). The MALAT1-mascRNA system is particularly interesting in this regard, since the 7-kb primary transcript localizes to the nucleus (Tripathi et al., 2010), whereas the small MALAT1-derived mascRNA is found exclusively in the cytoplasm. MALAT1 has not previously been studied in the context of infectious or immunological diseases, but it is highly expressed in tumors and associated with metastasis (Nakagawa et al., 2012). Recent studies additionally report that MALAT1 regulates endothelial cell functions and angiogenesis in vitro and in vivo (Michalik et al., 2014). For the first time, our new data now indicate that the MALAT1-mascRNA system has important immunoregulatory functions as well. Moreover, we document regulatory and functional dichotomy in the MALAT1-mascRNA system, which may also exist in otherlncRNAsystemsanddeservesfurtherattention when possible pathogenic relevance of lncRNAs is addressed. First, we compared myocardial transcriptomes in two groups of CVB3 cardiomyopathy patients, one of which eliminated CVB3 spontaneously (Cox-ELIM), whereas the other showed CVB3 persistence and clinical deterioration (Cox-PERS). At initial presentation, when transcriptomes were determined without knowledge of subsequent course, there was no significant difference in clinical parameters between these groups. Initial transcriptomes showed a relatively small number of transcripts differing between Cox-ELIM and Cox-PERS hearts. lncRNAs MALAT1 and nuclear paraspeckle assembly transcript 1 (NEAT1) were the most strongly deregulated transcripts (Supplementary Figure S1 and Table S1).

Second, we characterized expression levels of MALAT1 and NEAT1 and their processing products mascRNA and menRNA in human organs and peripheral blood mononuclear cells (PBMCs). Considering the highly stable tRNA-like structure of mascRNA and menRNA, we used northern blot analysis for its quantification and characterization including the detection of the different isoforms of mascRNA with or without CCA trinucleotide tail. Whereas the major transcripts of MALAT1 (7 kb) and NEAT1 (23 kb isoform) were highly abundant in all tissues and cell types studied (Figure 1 A), high levels of mascRNA (Figure 1 B) but not menRNA (Imamura et al., 2014)(Supplementary Figure S2A) were detected only in circulating human PBMCs. Analysis of CD3+, CD56+, CD19+, and CD14+ subpopulations showed that CD14+ monocytic cells express particularly