A Large Fraction of Extragenic RNA Pol II Transcription Sites Overlap Enhancers

Long noncoding RNAs (lncRNAs) comprise a diverse class of transcripts that structurally resemble mRNAs but do not encode proteins. Recent genome-wide studies in humans and the mouse have annotated lncRNAs expressed in cell lines and adult tissues, but a systematic analysis of lncRNAs expressed during vertebrate embryogenesis has been elusive. To identify lncRNAs with potential functions in vertebrate embryogenesis, we performed a time-series of RNA-seq experiments at eight stages during early zebrafish development. We reconstructed 56,535 high-confidence transcripts in 28,912 loci, recovering the vast majority of expressed RefSeq transcripts while identifying thousands of novel isoforms and expressed loci. We defined a stringent set of 1133 noncoding multi-exonic transcripts expressed during embryogenesis. These include long intergenic ncRNAs (lincRNAs), intronic overlapping lncRNAs, exonic antisense overlapping lncRNAs, and precursors for small RNAs (sRNAs). Zebrafish lncRNAs share many of the characteristics of their mammalian counterparts: relatively short length, low exon number, low expression, and conservation levels comparable to that of introns. Subsets of lncRNAs carry chromatin signatures characteristic of genes with developmental functions. The temporal expression profile of lncRNAs revealed two novel properties: lncRNAs are expressed in narrower time windows than are protein-coding genes and are specifically enriched in early-stage embryos. In addition, several lncRNAs show tissue-specific expression and distinct subcellular localization patterns. Integrative computational analyses associated individual lncRNAs with specific pathways and functions, ranging from cell cycle regulation to morphogenesis. Our study provides the first systematic identification of lncRNAs in a vertebrate embryo and forms the foundation for future genetic, genomic, and evolutionary studies.

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“…7B). Such overlapping lncRNAs might resemble enhancer-associated lncRNAs (De Santa et al 2010;Kim et al 2010;Ørom et al 2010;). …”

Section: Nearest Neighbor Analysis Of Lncrna Genesmentioning

confidence: 99%

Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis

Pauli¹,

Valen²,

Lin³

et al. 2011

Genome Res.

739

830

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“…One unanticipated observation that emerged from multiple global studies of RNA polymerase II (Pol II) occupancy was that Pol II binds to a large number of intergenic AR-bound enhancers marked by histone H3 lysine 4 monomethylation (H3K4me1) and lysine 27 acetylation (H3K27ac) and produces enhancer-derived long noncoding RNAs (eRNAs) (8)(9)(10)(11). Although eRNAs are bidirectional and nonpolyadenylated, their induction correlates with the induction of adjacent exon-coding genes (9).…”

Section: Klk3e/ar/med1 Complex | Chromosomal Loopingmentioning

confidence: 99%

Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation

Hsieh

Teng

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

339

364

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The androgen receptor (AR) is a key factor that regulates the behavior and fate of prostate cancer cells. The AR-regulated network is activated when AR binds enhancer elements and modulates specific enhancer-promoter looping. Kallikrein-related peptidase 3 (KLK3), which codes for prostate-specific antigen (PSA), is a wellknown AR-regulated gene and its upstream enhancers produce bidirectional enhancer RNAs (eRNAs), termed KLK3e. Here, we demonstrate that KLK3e facilitates the spatial interaction of the KLK3 enhancer and the KLK2 promoter and enhances long-distance KLK2 transcriptional activation. KLK3e carries the core enhancer element derived from the androgen response element III (ARE III), which is required for the interaction of AR and Mediator 1 (Med1). Furthermore, we show that KLK3e processes RNA-dependent enhancer activity depending on the integrity of core enhancer elements. The transcription of KLK3e was detectable and its expression is significantly correlated with KLK3 (R 2 = 0.6213, P < 5 × 10 −11 ) and KLK2 (R 2 = 0.5893, P < 5 × 10 −10 ) in human prostate tissues. Interestingly, RNAi silencing of KLK3e resulted in a modest negative effect on prostate cancer cell proliferation. Accordingly, we report that an androgen-induced eRNA scaffolds the AR-associated protein complex that modulates chromosomal architecture and selectively enhances AR-dependent gene expression.KLK3e/AR/Med1 complex | chromosomal looping

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“…More globally, a recent comprehensive screen identified dozens of lincRNAs required to maintain pluripotency and suggested that these lincRNAs work in trans . Another class of ''enhancer RNAs'' may either be by-products of transcription (De Santa et al 2010;Kim et al 2010) or serve to activate gene expression in cis (Orom et al 2010;Wang et al 2011). Despite these intriguing studies of individual lincRNAs, generalizing these findings to thousands of lincRNAs remains a substantial challenge.…”

mentioning

confidence: 99%

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

Cabili¹,

Trapnell²,

Goff³

et al. 2011

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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.

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A Large Fraction of Extragenic RNA Pol II Transcription Sites Overlap Enhancers

Abstract: A substantial fraction of extragenic Pol II transcription sites coincides with transcriptional enhancers, which may be relevant for functional annotation of mammalian genomes.

Cited by 804 publications

References 79 publications

Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis

Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis

Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation

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

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