Gene Loops Enhance Transcriptional Directionality

Tan-Wong, Sue Mei; Zaugg, Judith B.; Camblong, Jurgi; Xu, Zhenyu; Zhang, David W.; Mischo, Hannah E.; Ansari, Aseem Z.; Luscombe, Nicholas M.; Steinmetz, Lars M.; Proudfoot, Nick J.

doi:10.1126/science.1224350

Cited by 222 publications

(251 citation statements)

References 41 publications

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“…One possibility is that in the absence of retinoic acid, the Hoxa cluster adopts a conformation in which linc-HOXA1 is physically proximal to the Hoxa1 locus, but upon addition of retinoic acid, the binding of the retinoic acid receptor to its binding site (and subsequent activation) induces a conformational change that pulls linc-HOXA1 away from the Hoxa1 locus, thereby making that regulatory interaction impossible. Indeed, several other results have suggested a relationship between cis regulation by lncRNAs and chromosome structure (Zhang et al 2009;Ørom and Shiekhattar 2011;Wang et al 2011;Lee 2012;Tan-Wong et al 2012;Lai et al 2013), and we further note the excellent work of Petruk et al (2006) in which the investigators demonstrate regulation in Drosophila Hox genes by a lncRNA over a distance scale similar to that which we observed here. Such an interpretation is certainly consistent with our results showing that upon addition of retinoic acid, the correlation between linc-HOXA1 and Hoxa1 disappears, and linc-HOXA1 RNA knockdown produces no effect.…”

Section: Discussionsupporting

confidence: 65%

linc-HOXA1 is a noncoding RNA that represses Hoxa1 transcription in cis

et al. 2013

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Recently, researchers have uncovered the presence of many long noncoding RNAs (lncRNAs) in embryonic stem cells and believe they are important regulators of the differentiation process. However, there are only a few examples explicitly linking lncRNA activity to transcriptional regulation. Here, we used transcript counting and spatial localization to characterize a lncRNA (dubbed linc-HOXA1) located~50 kb from the Hoxa gene cluster in mouse embryonic stem cells. Single-cell transcript counting revealed that linc-HOXA1 and Hoxa1 RNA are highly variable at the single-cell level and that whenever linc-HOXA1 RNA abundance was high, Hoxa1 mRNA abundance was low and vice versa. Knockdown analysis revealed that depletion of linc-HOXA1 RNA at its site of transcription increased transcription of the Hoxa1 gene cis to the chromosome and that exposure of cells to retinoic acid can disrupt this interaction. We further showed that linc-HOXA1 RNA represses Hoxa1 by recruiting the protein PURB as a transcriptional cofactor. Our results highlight the power of transcript visualization to characterize lncRNA function and also suggest that PURB can facilitate lncRNA-mediated transcriptional regulation.

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Section: Discussionsupporting

confidence: 65%

linc-HOXA1 is a noncoding RNA that represses Hoxa1 transcription in cis

et al. 2013

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“…For example, in yeast and mammalian cells, it has been observed that transcription at protein-coding promoters often initiates bidirectionally, whereas bidirectional transcription is infrequent in Drosophila (Core et al 2008;Neil et al 2009;Seila et al 2009;Xu et al 2009;Nechaev et al 2010;Flynn et al 2011;Kharchenko et al 2011;Wei et al 2011). How bidirectional transcription initiation drives productive transcription elongation primarily in the coding direction is not well understood (Seila et al 2008(Seila et al , 2009Flynn et al 2011), but a recent report has suggested that gene loops can play a role (Tan-Wong et al 2012). In addition, it has been shown that mammalian enhancer regions are transcribed, but transcription initiation within enhancer regions has not been well characterized (De Santa et al 2010;Kim et al 2010;Melgar et al 2011;Ong and Corces 2011;Preker et al 2011;Wang et al 2011).…”

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confidence: 99%

The landscape of RNA polymerase II transcription initiation in C. elegans reveals promoter and enhancer architectures

et al. 2013

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RNA polymerase transcription initiation sites are largely unknown in Caenorhabditis elegans. The initial 59 end of most protein-coding transcripts is removed by trans-splicing, and noncoding initiation sites have not been investigated. We characterized the landscape of RNA Pol II transcription initiation, identifying 73,500 distinct clusters of initiation. Bidirectional transcription is frequent, with a peak of transcriptional pairing at 120 bp. We assign transcription initiation sites to 7691 protein-coding genes and find that they display features typical of eukaryotic promoters. Strikingly, the majority of initiation events occur in regions with enhancer-like chromatin signatures. Based on the overlap of transcription initiation clusters with mapped transcription factor binding sites, we define 2361 transcribed intergenic enhancers. Remarkably, productive transcription elongation across these enhancers is predominantly in the same orientation as that of the nearest downstream gene. Directed elongation from an upstream enhancer toward a downstream gene could potentially deliver RNA polymerase II to a proximal promoter, or alternatively might function directly as a distal promoter. Our results provide a new resource to investigate transcription regulation in metazoans.

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“…Interactions in cis are also clearly important for transcriptional terminators, since a sequence can only be used to terminate a transcript if it is first transcribed. Moreover, the existence of physical connections between the 59 and 39 ends of genes that depend on proper 39 end formation (Ansari and Hampsey 2005;Tan-Wong et al 2012) suggests the existence of a feedback mechanism between terminators and promoters.…”

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confidence: 99%

A unified model for yeast transcript definition

Boer¹,

Bakel

Tsui

et al. 2013

Genome Res.

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Identifying genes in the genomic context is central to a cell's ability to interpret the genome. Yet, in general, the signals used to define eukaryotic genes are poorly described. Here, we derived simple classifiers that identify where transcription will initiate and terminate using nucleic acid sequence features detectable by the yeast cell, which we integrate into a Unified Model (UM) that models transcription as a whole. The cis-elements that denote where transcription initiates function primarily through nucleosome depletion, and, using a synthetic promoter system, we show that most of these elements are sufficient to initiate transcription in vivo. Hrp1 binding sites are the major characteristic of terminators; these binding sites are often clustered in terminator regions and can terminate transcription bidirectionally. The UM predicts global transcript structure by modeling transcription of the genome using a hidden Markov model whose emissions are the outputs of the initiation and termination classifiers. We validated the novel predictions of the UM with available RNA-seq data and tested it further by directly comparing the transcript structure predicted by the model to the transcription generated by the cell for synthetic DNA segments of random design. We show that the UM identifies transcription start sites more accurately than the initiation classifier alone, indicating that the relative arrangement of promoter and terminator elements influences their function. Our model presents a concrete description of how the cell defines transcript units, explains the existence of nongenic transcripts, and provides insight into genome evolution.

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Gene Loops Enhance Transcriptional Directionality

Cited by 222 publications

References 41 publications

linc-HOXA1 is a noncoding RNA that represses Hoxa1 transcription in cis

linc-HOXA1 is a noncoding RNA that represses Hoxa1 transcription in cis

The landscape of RNA polymerase II transcription initiation in C. elegans reveals promoter and enhancer architectures

A unified model for yeast transcript definition

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