Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses

Abstract

Large intergenic noncoding RNAs (lincRNAs) are emerging as key regulators of diverse cellular processes. Determining the function of individual lincRNAs remains a challenge. Recent advances in RNA sequencing (RNA-seq) and computational methods allow for an unprecedented analysis of such transcripts. Here, we present an integrative approach to define a reference catalog of >8000 human lincRNAs. Our catalog unifies previously existing annotation sources with transcripts we assembled from RNA-seq data collected from~4 billion RNA-seq reads across 24 tissues and cell types. We characterize each lincRNA by a panorama of >30 properties, including sequence, structural, transcriptional, and orthology features. We found that lincRNA expression is strikingly tissue-specific compared with coding genes, and that lincRNAs are typically coexpressed with their neighboring genes, albeit to an extent similar to that of pairs of neighboring protein-coding genes. We distinguish an additional subset of transcripts that have high evolutionary conservation but may include short ORFs and may serve as either lincRNAs or small peptides. Our integrated, comprehensive, yet conservative reference catalog of human lincRNAs reveals the global properties of lincRNAs and will facilitate experimental studies and further functional classification of these genes.

Extensive microRNA-mediated crosstalk between lncRNAs and mRNAs in mouse embryonic stem cells

“…Nevertheless, some established ceRNAs neither share an unusually high number of predicted MREs with their mRNA targets nor are especially abundant (Cesana et al 2011;Wang et al 2013), which suggests that other factors, such as miRNA-target affinity or miRNA turnover, might explain their efficient crosstalk. These ceRNAs are also no different from most other lncRNAs (Cabili et al 2011;Derrien et al 2012) with respect to their highly restricted spatial and temporal expression patterns. For example, linc-MD1 is a muscle-specific ceRNA that regulates transcript abundance of two key myogenic transcription factors, Maml1 and Mef2c, which are required for activating muscle-specific gene expression (Cesana et al 2011); in addition, linc-RoR competes for miR-145 binding with key self-renewal transcription factor transcripts, namely Nanog, Pou5f1, and Sox2, and is expressed during induced pluripotent stem cell (iPSC) reprogramming and in undifferentiated embryonic stem cells (ESCs) (Loewer et al 2010;Wang et al 2013).…”

“…The relatively low transcript abundance of most lncRNAs (Cabili et al 2011;Derrien et al 2012) might be thought to limit their ability to effectively modulate, in a miRNA-dependent manner, mRNA abundance (Ebert and Sharp 2010;Ala et al 2013;Figliuzzi et al 2013;Denzler et al 2014). Nevertheless, some established ceRNAs neither share an unusually high number of predicted MREs with their mRNA targets nor are especially abundant (Cesana et al 2011;Wang et al 2013), which suggests that other factors, such as miRNA-target affinity or miRNA turnover, might explain their efficient crosstalk.…”

Genome-Wide Analysis Uncovers Regulation of Long Intergenic Noncoding RNAs in Arabidopsis

“…lincRNAs have been described in yeast as well as higher eukaryotes (Bumgarner et al, 2009;Khalil et al, 2009;Ulitsky et al, 2011), and genome-wide analysis has uncovered more than 8000 lincRNA genes in the human genome (Khalil et al, 2009;Chen and Carmichael, 2010;Cabili et al, 2011). Mammalian lincRNAs are suggested to be transcribed by RNA polymerase II and processed by both 59-capping and 39 poly(A) addition (Guttman et al, 2009), and many contain introns (Managadze et al, 2011;Ulitsky et al, 2011).…”

“…Mammalian lincRNAs are suggested to be transcribed by RNA polymerase II and processed by both 59-capping and 39 poly(A) addition (Guttman et al, 2009), and many contain introns (Managadze et al, 2011;Ulitsky et al, 2011). lincRNAs are expressed in a tissue-specific manner, and many lincRNA genes are regulated by stress (Dinger et al, 2008;Cabili et al, 2011). Moreover, ;20% of the 3300 lincRNAs in human cells are associated with polycomb repressor complex 2 (Hekimoglu and Ringrose, 2009).…”

Human Lymphoid Translocation Fragile Zones Are Hypomethylated and Have Accessible Chromatin

“…We have also carried out bioinformatics analyses for transcription factor binding sites, noncoding RNA, and histone modifications in the publically available data set from human mature B cells and other human B-linage cells, and known locations for these did not correlate with the fragile zones (see Fig. S9 to S12 in the supplemental material) (37,38). However, the BCL2-MBR, CCND1-MTC, and MALT1 regions are nearly fully methylated in the H1 human embryonic stem cell line based on the publicly available genome-wide sodium bisulfite sequencing data set (GEO Accession Viewer no.…”