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.
Intron retention (IR) in cancer was for a long time overlooked by the scientific community, as it was previously considered to be an artifact of a dysfunctional spliceosome. Technological advancements made in the last decade offer unique opportunities to explore the role of IR as a widespread phenomenon that contributes to the transcriptional diversity of many cancers. Numerous studies in cancer have shed light on dysregulation of cellular mechanisms that lead to aberrant and pathologic IR. IR is not merely a mechanism of gene regulation, but rather it can mediate cancer pathogenesis and therapeutic resistance in various human diseases. The burden of IR in cancer is governed by perturbations to mechanisms known to regulate this phenomenon and include epigenetic variation, mutations within the gene body, and splicing factor dysregulation. This review summarizes possible causes for aberrant IR and discusses the role of IR in therapy or as a consequence of disease treatment. As neoepitopes originating from retained introns can be presented on the cancer cell surface, the development of personalized cancer vaccines based on IR-derived neoepitopes should be considered. Ultimately, a deeper comprehension about the origins and consequences of aberrant IR may aid in the development of such personalized cancer vaccines.
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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