Jernej Ule

The Francis Crick Institute

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Nicholas M. Luscombe

Okinawa Institute of Science and Technology Graduate University

Tomaž Curk

University of Ljubljana

Julian König

Institute of Molecular Biology

Charlotte Capitanchik

The Francis Crick Institute

Anob M. Chakrabarti

The Francis Crick Institute

Nejc Haberman

MRC London Institute of Medical Sciences

Christopher R. Sibley

University of Edinburgh

Flora Lee

Alaska Native Tribal Health Consortium

Rupert Faraway

University College London

Klara Kuret

The Francis Crick Institute

Cooperative Institutions

University College London

488

National Hospital for Neurology and Neurosurgery

388

The Francis Crick Institute

330

University College London Hospitals NHS Foundation Trust

292

University of Cambridge

185

Medical Research Council

113

Imperial College London

King's College London

Harvard University

University of Oxford

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Understanding splicing regulation through RNA splicing maps

Trends in Genetics (2011)

Joshua T. Witten Jernej Ule

Alternative splicing is a highly regulated process that greatly increases the proteome diversity and plays an important role in cellular differentiation and disease. Interactions between RNA-binding proteins (RBPs) and pre-mRNA are the principle regulator of splicing decisions. Findings from recent genome-wide studies of protein-RNA interactions have been combined with assays of the global effects of RBPs on splicing to create RNA splicing maps. These maps integrate information from all pre-mRNAs regulated by single RBPs to identify the global positioning principles guiding splicing regulation. Recent studies using this approach have identified a set of positional principles that are shared between diverse RBPs. Here, we discuss how insights from RNA splicing maps of different RBPs inform the mechanistic models of splicing regulation.

Proteome

Exonic splicing enhancer

Splicing factor

10.1016/j.tig.2010.12.001

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Citations (265)

A systems view of spliceosomal assembly and branchpoints with iCLIP

Nature Structural & Molecular Biology (2019)

Michael Briese Nejc Haberman Christopher R. Sibley Rupert Faraway Andrea S. Elser

10.1038/s41594-019-0300-4

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Citations (31)

Intergenic RNA mainly derives from nascent transcripts of known genes

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Federico Agostini Julian A. Zagalak Jan Attig Jernej Ule Nicholas M. Luscombe

Abstract Background Eukaryotic genomes undergo pervasive transcription, leading to the production of many types of stable and unstable RNAs. Transcription is not restricted to regions with annotated gene features but includes almost any genomic context. Currently, the source and function of most RNAs originating from intergenic regions in the human genome remains unclear. Results We hypothesised that many intergenic RNA can be ascribed to the presence of as-yet unannotated genes or the ‘fuzzy’ transcription of known genes that extends beyond the annotated boundaries. To elucidate the contributions of these two sources, we assembled a dataset of >2.5 billion publicly available RNA-seq reads across 5 human cell lines and multiple cellular compartments to annotate transcriptional units in the human genome. About 80% of transcripts from unannotated intergenic regions can be attributed to the fuzzy transcription of existing genes; the remaining transcripts originate mainly from putative long non-coding RNA loci that are rarely spliced. We validated the transcriptional activity of these intergenic RNA using independent measurements, including transcriptional start sites, chromatin signatures, and genomic occupancies of RNA polymerase II in various phosphorylation states. We also analysed the nuclear localisation and sensitivities of intergenic transcripts to nucleases to illustrate that they tend to be rapidly degraded either ‘on-chromatin’ by XRN2 or ‘off-chromatin’ by the exosome. Conclusions We provide a curated atlas of intergenic RNAs that distinguishes between alternative processing of well annotated genes from independent transcriptional units based on the combined analysis of chromatin signatures, nuclear RNA localisation and degradation pathways.

Intergenic region

Transcription

Pseudogene

10.1101/2020.01.08.898478

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Citations (1)

Erratum to: Insights into the design and interpretation of iCLIP experiments

Genome biology (2017)

Nejc Haberman Ina Huppertz Jan Attig Julian König Zhen Wang

Human genetics

Genome Biology

10.1186/s13059-017-1294-z

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Citations (1)

Additional file 8 of Positional motif analysis reveals the extent of specificity of protein-RNA interactions observed by CLIP

Figshare (2022)

Klara Kuret Aram Gustav Amalietti D. Marc Jones Charlotte Capitanchik Jernej Ule

Additional file 8: Table S7, which includes recall values for eCLIP datasets analysed with PEKA (using Clippy peaks or narrowPeaks), eCLIP datasets analysed with mCross, as well as iCLIP and PAR-CLIP datasets analysed with PEKA (using Clippy peaks) (related to Figs. 2, 3, 4, 5, 6 and Additional file 1: Fig. S3, S5, S6).

Motif (music)

Structural motif

10.6084/m9.figshare.21077352

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Additional file 6 of Positional motif analysis reveals the extent of specificity of protein-RNA interactions observed by CLIP

Figshare (2022)

Klara Kuret Aram Gustav Amalietti D. Marc Jones Charlotte Capitanchik Jernej Ule

Additional file 6: Table S5, which lists 5-mer ranks for all datasets used in this study, i.e. eCLIP datasets analysed with PEKA (using Clippy peaks or narrowPeaks), eCLIP datasets analysed with mCross, eCLIP and PAR-CLIP datasets analysed with ‘local’ approach, as well as iCLIP, PAR-CLIP, RBNS and RNAC datasets. For RBNS, RNAC and mCross, additional data are available, which are not shown in the Figures.

Motif (music)

10.6084/m9.figshare.21077346

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A Global Regulatory Mechanism for Activating an Exon Network Required for Neurogenesis

Molecular Cell (2014)

Bushra Raj Manuel Irimia Ulrich Braunschweig Timothy Sterne-Weiler Dave O’Hanlon

10.1016/j.molcel.2014.08.011

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Citations (133)

Lactate Potentiates Differentiation and Expansion of Cytotoxic T Cells

SSRN Electronic Journal (2019)

Helene Rundqvist Pedro Veliça Laura Barbieri Paulo A. Gameiro Pedro P. Cunha

Exercise has a wide range of systemic effects. In animal models, repeated exertion reduces malignant tumor progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effect of exercise on tumor progression is unclear, as are the cellular actors involved. We show here that exercise-induced reduction in tumor growth is dependent on CD8+ T cells and that lactate, which is produced at high levels during exertion, increases proliferative capacity and cytotoxicity of CD8+ T cells. We found that at elevated levels lactate is used as a fuel during T cell activation. We further found that daily injections of lactate into animals can reduce malignant tumor growth in a dose- and CD8+ T cell-dependent manner. These data demonstrate that lactate can act to enhance expansion of cytotoxic T cells and in so doing reduce cancer progression.

10.2139/ssrn.3411249

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Citations (3)

Human Integrator provides a quality checkpoint during elongation to facilitate RNA polymerase II processivity

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Sara Rohban Mahmoud‐Reza Rafiee Jernej Ule Nicholas M. Luscombe

Abstract Integrator is a multi-subunit complex that directly interacts with the C-terminal domain (CTD) of RNA polymerase II (RNAPII). Through its RNA endonuclease activity, Integrator is required for 3′-end processing of both non-coding and coding transcripts. Here we demonstrate that depleting Integrator subunit 11 (INTS11), the main catalytic subunit of the Integrator complex, leads to a global elongation defect as a result of decreased polymerase processivity. We observe this defect in the region approximately 12 to 35 kb downstream of the transcription start site (TSS), where RNAPII normally transitions to its maximum processivity. We also identify an important role for INTS11, possibly in association with RNAPII CTD phospho-Tyr1, in repressing antisense transcription upstream of active promoters, as well as repressing transcription of genic regions near AsiSI-induced double-strand breaks. Altogether, this study points toward a novel function of Integrator in promoting termination of incompetent RNAPII molecules while facilitating the transition to fully processive polymerase in order to enable efficient elongation.

Processivity

RNA polymerase II

Transcription

10.1101/2023.02.17.528960

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Citations (8)

hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1

Nature (2015)

Yoichiro Sugimoto Alessandra Vigilante Élodie Darbo Alexandra Zirra Cristina Militti

Nucleic acid structure

RNA Silencing

10.1038/nature14280

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Citations (270)