Holding on to Junk Bonds: Intron Retention in Cancer and Therapy

Monteuuis, Geoffray; Schmitz, Ulf; Petrova, Veronika; Kearney, Padraic Scott; Rasko, John E.J.

doi:10.1158/0008-5472.can-20-1943

Cited by 21 publications

(19 citation statements)

References 103 publications

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“…Future analyses will seek to explore correlations between transcriptomic and genomic data and cellular or developmental phenotypes. Moreover, given the extensive characterization of CTCF as a tumor suppressor gene ( 120 , 136 , 141–143 ), its frequent mutation in cancer ( 133 , 134 , 136 ) and loss- or gain-of-function phenotypes ( 135 ), causal links between CTCF-mediated aberrant AS and cancer are likely to emerge ( 144 , 145 ).…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

CTCF as a regulator of alternative splicing: new tricks for an old player

Alharbi

Schmitz

Bailey

et al. 2021

Nucleic Acids Research

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Three decades of research have established the CCCTC-binding factor (CTCF) as a ubiquitously expressed chromatin organizing factor and master regulator of gene expression. A new role for CTCF as a regulator of alternative splicing (AS) has now emerged. CTCF has been directly and indirectly linked to the modulation of AS at the individual transcript and at the transcriptome-wide level. The emerging role of CTCF-mediated regulation of AS involves diverse mechanisms; including transcriptional elongation, DNA methylation, chromatin architecture, histone modifications, and regulation of splicing factor expression and assembly. CTCF thereby appears to not only co-ordinate gene expression regulation but contributes to the modulation of transcriptomic complexity. In this review, we highlight previous discoveries regarding the role of CTCF in AS. In addition, we summarize detailed mechanisms by which CTCF mediates AS regulation. We propose opportunities for further research designed to examine the possible fate of CTCF-mediated alternatively spliced genes and associated biological consequences. CTCF has been widely acknowledged as the ‘master weaver of the genome’. Given its multiple connections, further characterization of CTCF’s emerging role in splicing regulation might extend its functional repertoire towards a ‘conductor of the splicing orchestra’.

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Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

CTCF as a regulator of alternative splicing: new tricks for an old player

Alharbi

Schmitz

Bailey

et al. 2021

Nucleic Acids Research

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“…Fates of intron-retaining transcripts can be diverse and include (i) nonsense-mediated decay triggered by intronic premature termination codons, (ii) detention in the nucleus or nuclear degradation, and (iii) translation into alternative protein isoforms or creation of neoepitopes (Monteuuis et al, 2019; Smart et al, 2018; Wong et al, 2016). A better understanding of how IR is regulated is crucial to determine factors leading to aberrant IR, which has been associated with multiple diseases including cancer (Dvinge et al, 2019; Hershberger et al, 2020; Monteuuis et al, 2020)…”

Section: Introductionmentioning

confidence: 99%

“…Despite numerous studies that describe the role of retained introns in key biological functions in animals and in human diseases (Monteuuis et al, 2020; Monteuuis et al, 2019; Wong et al, 2016), a comprehensive understanding of their regulation is still lacking. Retained introns have conserved intrinsic characteristics such as a higher GC content, shorter lengths, and weaker splice sites in comparison to their non-retained counterparts (Braunschweig et al, 2014; Monteuuis et al, 2019; Schmitz et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Chromatin accessibility determines intron retention in a cell type-specific manner

Petrova

Song

Nordström

et al. 2021

Preprint

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Background: The phenomenon of widespread and dynamic intron retention (IR) programs in cells of vertebrate species has recently gained increasing attention. It has been shown that IR is involved in a multitude of cell-physiological processes, while aberrant IR profiles have been associated with numerous human diseases including several cancers. Gap: Despite consistent reports about intrinsic sequence features that predispose introns to become retained, conflicting findings about cell type or condition-specific IR regulation by trans-regulatory and epigenetic mechanisms demand an unbiased and systematic analysis of IR in a controlled experimental setting. Methods: We integrated matched mRNA sequencing (RNA-seq), whole genome bisulfite sequencing (WGBS), nucleosome occupancy methylome sequencing (NOMe-Seq), and chromatin immunoprecipitation sequencing (ChIP-seq) data from primary human myeloid and lymphoid cells. Using these multi-omics data and machine learning we trained two complementary models to determine the role of epigenetic factors in the regulation of IR in cells of the innate immune system. Results: Our results show that intrinsic characteristics are key for introns to evade splicing and that some epigenetic marks are associated with IR. However, cell type-specific IR profiles are largely marked by changes in chromatin accessibility, whereby predisposed introns in permissive chromatin regions are more likely to be retained. Conclusion: This study demonstrates the important role of chromatin architecture in IR regulation. Our results have profound implications for the analysis of other forms of alternative splicing as well. Since an increasing number of studies describe pathogenic alterations in splicing regulation and novel therapeutic approaches that target aberrant splicing, our findings will inform the development of novel epigenetic therapies. Keywords: nucleosome occupancy, intron retention, epigenetics, alternative splicing, histone marks, CpG methylation, chromatin accessibility

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“…While the effect of persisting leukemic clones on aberrant splicing cannot be entirely ruled out, our evidence suggests that this is unlikely to be the case. Multiple recent studies have shown that aberrant IR in cancer can be triggered by epigenetic changes, splicing factor dysregulation and changes in transcription elongation [ 47 ]. We confirmed these observations in our analysis of CML patient samples and K562 cells.…”

Section: Discussionmentioning

confidence: 99%

Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients

Schmitz

Shah

Dhungel

et al. 2020

Cancers

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Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukaemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Using RNA sequencing and whole-genome bisulfite sequencing, we profiled samples from chronic-phase CML patients at diagnosis and remission and compared these to healthy donors. Remarkably, our analyses revealed that abnormal splicing distinguishes remission samples from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis samples. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease.

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Holding on to Junk Bonds: Intron Retention in Cancer and Therapy

Cited by 21 publications

References 103 publications

CTCF as a regulator of alternative splicing: new tricks for an old player

CTCF as a regulator of alternative splicing: new tricks for an old player

Chromatin accessibility determines intron retention in a cell type-specific manner

Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients

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