The complex eukaryotic transcriptome: unexpected pervasive transcription and novel small RNAs

Jacquier, Alain

doi:10.1038/nrg2683

Cited by 392 publications

(325 citation statements)

References 79 publications

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“…Argonaute proteins have been profusely studied and characterized for their cytoplasmic roles as mediators of posttranscriptional gene silencing mediated by siRNAs and microRNAs (30)(31)(32)(33). The existence of specific nuclear roles for these proteins in mammalian cells was demonstrated at the individual gene level for the mechanism of transcriptional gene silencing either acting at the promoter level (18,34,35) or intragenically in the regulation of alternative splicing (3,10,23).…”

Section: Discussionmentioning

confidence: 99%

Argonaute-1 binds transcriptional enhancers and controls constitutive and alternative splicing in human cells

Alló

Agirre

Bessonov

et al. 2014

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

103

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The roles of Argonaute proteins in cytoplasmic microRNA and RNAi pathways are well established. However, their implication in small RNA-mediated transcriptional gene silencing in the mammalian cell nucleus is less understood. We have recently shown that intronic siRNAs cause chromatin modifications that inhibit RNA polymerase II elongation and modulate alternative splicing in an Argonaute-1 (AGO1)-dependent manner. Here we used chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) to investigate the genome-wide distribution of AGO1 nuclear targets. Unexpectedly, we found that about 80% of AGO1 clusters are associated with cell-type-specific transcriptional enhancers, most of them (73%) overlapping active enhancers. This association seems to be mediated by long, rather than short, enhancer RNAs and to be more prominent in intragenic, rather than intergenic, enhancers. Paradoxically, crossing ChIP-seq with RNA-seq data upon AGO1 depletion revealed that enhancer-bound AGO1 is not linked to the global regulation of gene transcription but to the control of constitutive and alternative splicing, which was confirmed by an individual gene analysis explaining how AGO1 controls inclusion levels of the cassette exon 107 in the SYNE2 gene.Argonaute proteins | transcriptional enhancers | alternative splicing A lternative splicing was initially seen as an interesting mechanism to explain protein diversity but affecting a limited number of mammalian genes. The recent development of high-throughput sequencing technologies has dramatically changed this view, generating a renewed interest in alternative splicing. We now know that alternative splicing affects transcripts from more than 90% of human genes (1) and that normal and pathological cell differentiation not only depends on differential gene expression but also on alternative splicing patterns. Mutations in alternative splicing regulatory sequences and factors are involved in the etiology of numerous hereditary diseases, premature aging, and cancer (2).Recently, amid an avalanche of papers reporting various connections between the chromatin context and splicing (3-9), a relationship between splicing and small RNAs has emerged. The convergence of these previously unrelated areas (RNA interference, chromatin, and splicing) has been studied by our laboratory, showing that siRNAs (20-25 nt long) targeting both intronic and exonic regions near the cassette exon 33 (E33, also known as EDI) of the fibronectin gene were able to regulate its alternative splicing by affecting the chromatin context at the target region, with an increase of histone tail modifications associated with gene silencing (H3K9me2 and H3K27me3, i.e., dimethylation of lysine 9 and trimethylation of lysine 27 of histone H3 respectively). Moreover, this effect was shown to be dependent on Argonaute proteins (AGO1 and AGO2) and involves a decrease of RNA polymerase II (RNAPII) elongation, which concomitantly up-regulates E33 inclusion into the mature mRNA (3). More recently, a similar effect was fou...

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Section: Discussionmentioning

confidence: 99%

Argonaute-1 binds transcriptional enhancers and controls constitutive and alternative splicing in human cells

Alló

Agirre

Bessonov

et al. 2014

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

103

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“…Transcriptome analysis unveiled that the pervasive transcription occurs in animal and yeast cells with defective exosome alleles (Jacquier, 2009). In animal cells many different RNAs have been discovered by using different techniques.…”

Section: Bi-directional Transcription and Rna Decaymentioning

confidence: 99%

mRNA stability in the nucleus

Liu

Luo

Wen

2014

J. Zhejiang Univ. Sci. B

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Abstract:Eukaryotic gene expression is controlled by different levels of biological events, such as transcription factors regulating the timing and strength of transcripts production, alteration of transcription rate by RNA processing, and mRNA stability during RNA processing and translation. RNAs, especially mRNAs, are relatively vulnerable molecules in living cells for ribonucleases (RNases). The maintenance of quality and quantity of transcripts is a key issue for many biological processes. Extensive studies draw the conclusion that the stability of RNAs is dedicated-regulated, occurring co-and post-transcriptionally, and translation-coupled as well, either in the nucleus or cytoplasm. Recently, RNA stability in the nucleus has aroused much research interest, especially the stability of newly-made transcripts. In this article, we summarize recent progresses on mRNA stability in the nucleus, especially focusing on quality control of newly-made RNA by RNA polymerase II in eukaryotes.

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“…The ability to manipulate the properties of RNA using engineered RNA-binding proteins is an attractive prospect for biotechnological and therapeutic applications. Furthermore, the need for new methods to determine the functions of RNAs has become even more critical given the unprecedented complexity of cellular transcriptomes that has recently been revealed using massively parallel sequencing [3][4][5] . Although robust technologies have now emerged that enable the site-specific manipulation of DNA in living cells 6 , equivalent technologies for the manipulation of RNA are still in their infancy 7 .…”

mentioning

confidence: 99%

An artificial PPR scaffold for programmable RNA recognition

et al. 2014

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Pentatricopeptide repeat (PPR) proteins control diverse aspects of RNA metabolism in eukaryotic cells. Although recent computational and structural studies have provided insights into RNA recognition by PPR proteins, their highly insoluble nature and inconsistencies between predicted and observed modes of RNA binding have restricted our understanding of their biological functions and their use as tools. Here we use a consensus design strategy to create artificial PPR domains that are structurally robust and can be programmed for sequence-specific RNA binding. The atomic structures of these artificial PPR domains elucidate the structural basis for their stability and modelling of RNA-protein interactions provides mechanistic insights into the importance of RNA-binding residues and suggests modes of PPR-RNA association. The modular mode of RNA binding by PPR proteins holds great promise for the engineering of new tools to target RNA and to understand the mechanisms of gene regulation by natural PPR proteins.

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The complex eukaryotic transcriptome: unexpected pervasive transcription and novel small RNAs

Cited by 392 publications

References 79 publications

Argonaute-1 binds transcriptional enhancers and controls constitutive and alternative splicing in human cells

Argonaute-1 binds transcriptional enhancers and controls constitutive and alternative splicing in human cells

mRNA stability in the nucleus

An artificial PPR scaffold for programmable RNA recognition

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