Regulation of Alternative Splicing by Histone Modifications

Luco, Reini F.; Pan, Qun; Tominaga, Kaoru; Blencowe, Benjamin J.; Pereira‐Smith, Olivia M.; Misteli, Tom

doi:10.1126/science.1184208

Cited by 949 publications

(1,048 citation statements)

References 27 publications

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“…Second, enzymes that modify histones to modulate the accessibility of specific genetic loci to the transcriptional machinery can also modulate AS events through binding small nuclear ribonucleoproteins components of the spliceosome (reviewed in Luco et al 2011). For example, EMT-associated decreases in FGFR2 histone 3 lysine 27 trimethylation (H3K27me3) and H3K4me3, and increases in H3K36me3 and H3K4me1 was shown to causally promote the corresponding FGFR2 splice switch discussed above (Luco et al 2010).…”

Section: Resultsmentioning

confidence: 99%

Post-transcriptional regulation in cancer progression

Jewer

Findlay

Postovit

2012

J. Cell Commun. Signal.

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The microenvironment acts as a conduit for cellular communication, delivering signals that direct development and sustain tissue homeostasis. In pathologies such as cancer, this integral function of the microenvironment is hijacked to support tumor growth and progression. Cells sense the microenvironment via signal transduction pathways culminating in altered gene expression. In addition to induced transcriptional changes, the microenvironment exerts its effect on the cell through regulation of posttranscriptional processes including alternative splicing and translational control. Here we describe how alternative splicing and protein translation are controlled by microenvironmental parameters such as oxygen availability. We also emphasize how these pathways can be utilized to support processes that are hallmarks of cancer such as angiogenesis, proliferation, and cell migration. We stress that cancer cells respond to their microenvironment through an integrated regulation of gene expression at multiple levels that collectively contribute to disease progression.

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Section: Resultsmentioning

confidence: 99%

Post-transcriptional regulation in cancer progression

Jewer

Findlay

Postovit

2012

J. Cell Commun. Signal.

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“…Thus, it has been shown that differential enrichment for specific histone H3 modifications regulates the tissue-specificity of alternative splicing in the fibroblast growth factor receptor 2 gene (FGFR2 ) [31]. Also, allele-specific DNA methylation established during gametogenesis at imprinting sequences could lead to allele-specific polyadenylation as it occurs at the imprinted Herc3/Nap1l5 [32] and Mcts2/H13 [33] loci.…”

Section: Methylationmentioning

confidence: 99%

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

2013

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The most fundamental roles of non-coding RNAs (ncRNAs) and epigenetic mechanisms are the guidance of cellular differentiation in development and the regulation of gene expression in adult tissues. In brain, both ncRNAs and the various epigenetic gene regulatory mechanisms play a fundamental role in neurogenesis and normal neuronal function. Thus, epigenetic chromatin remodelling can render coding sites transcriptionally inactive by DNA methylation, histone modifications or antisense RNA interactions. On the other hand, microRNAs (miRNAs) are ncRNA molecules that can regulate the expression of hundreds of genes post-transcriptionally, typically recognising binding sites in the 3′ untranslated region (UTR) of mRNA transcripts. Furthermore, there are a myriad of interactions in the interface of miRNAs and epigenetics. For example, epigenetic mechanisms can silence miRNA coding sites, and miRNAs can be the effectors of transcriptional gene silencing, targeting complementary promoters or silencing the expression of epigenetic modifier genes like MECP2 and EZH2 leading to global changes in the epigenome. Alterations in this regulatory machinery play a key role in the pathology of complex disorders including cancer and neurological diseases. For example, miRNA genes are frequently inactivated by epimutations in gliomas. Here we describe the interactions between epigenetic and ncRNA regulatory systems and discuss therapeutic potential, with an emphasis on tumors, cognitive disorders and neurodegenerative diseases.

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“…Plusieurs catégories de tels agents peuvent être envisagées (pour revue, voir [45,46]) : -des molécules ciblant spécifiquement des protéines du splicéosome comme SF3B1 (spliceostatine, pladienolide, meayamycine), ainsi que de nombreuses autres ; -d'autres composés aux effets moins spécifiques sur l'épissage, comme le clotrimazole, l'indole, les dérivés de la diospyrine, ou encore les camptothécines, le butyrate ou le valproate de sodium ou le resvératrol. Du fait du couplage entre transcription et épissage, du rôle de modifications épigénétiques sur les activités transcriptionnelles et d'épissage [47], et de l'influence de paramètres épigénétiques sur l'activité du splicéo-some [48], il serait intéressant d'évaluer également le potentiel correctif de « drogues épigénétiques » additionnelles (inhibitrices des ADN méthyl-transférases par exemple).…”

Section: Abords Thérapeutiquesunclassified