A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature

González, Inma; Munita, Roberto; Agirre, Eneritz; Dittmer, Travis A.; Gysling, Katia; Misteli, Tom; Luco, Reini F.

doi:10.1038/nsmb.3005

Cited by 234 publications

(181 citation statements)

References 34 publications

(39 reference statements)

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“…In humans, KDM2 has two homologues (KDM2A and KDM2B) that demethylate H3K36me2 and repress transcription (41, 42). KDM2A interacts with SUZ12, a component of Polycomb repressive complex 2 (43). Overexpression of KDM2A reduced MLL-dependent transcription and leukemic transformation.…”

Section: Discussionmentioning

confidence: 99%

ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia

et al. 2016

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Numerous studies in multiple systems support that histone H3 lysine 36 di-methylation (H3K36me2) is associated with transcriptional activation, however the underlying mechanisms are not well defined. Here we show that the H3K36me2 chromatin mark written by the ASH1L histone methyltransferase is preferentially bound in vivo by LEDGF, an MLL-associated protein that co-localizes with MLL, ASH1L and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild type MLL proteins to chromatin at key leukemia target genes, and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely KDM2A, an H3K36me2 demethylase and Polycomb-group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies are the first to provide a basic mechanistic insight into epigenetic interactions wherein placement, interpretation and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a novel target for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia

et al. 2016

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“…Recently, lncRNAs have been shown to affect AS by different mechanisms, which provides cells with an additional level of complexity to the regulation of gene expression. 38,51,52 Extensive changes in AS of many mRNAs have been reported in EMT. 8,12 In the well-characterized family of FGFRs, it has been reported that FGFR1IIIc and FGFR2IIIb, respective isoforms of FGFR1 and FGFR2, are upregulated and downregulated, respectively, by TGF-β, producing NMuMG cells to be sensitive to FGF-2.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Lnc-Spry1 mediates TGF-β-induced epithelial–mesenchymal transition by transcriptional and posttranscriptional regulatory mechanisms

et al. 2017

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Long non-coding RNAs (lncRNAs) are a class of regulatory genes that participate in a wide range of biological processes, including proliferation, differentiation and development, as well as in a broad spectrum of diseases. Although the role of lncRNAs in TGF-β-induced epithelial-to-mesenchymal transition (EMT) has been well established, little is known about the role of lncRNAs as immediate-early regulators of EMT. Here lnc-Spry1 is identified as an immediate-early regulator of EMT that is downregulated by TGF-β. It is also found that knockdown of lnc-Spry1 promotes a mesenchymal-like phenotype and results in increased cell migration and invasion. In addition, it is shown that lnc-Spry1 depletion preferentially affects the expression of TGF-β-regulated gene targets. Moreover, lnc-Spry1 associates with U2AF65 splicing factor, suggesting a role in alternative splicing. Depletion of lnc-Spry1 induces, as TGF-β, isoform switching of fibroblast growth factor receptors, resulting in FGF-2-sensitive cells. Taken together, these results show that lnc-Spry1 could act as an early mediator of TGF-β signaling and reveal different roles for a lncRNA in modulating transcriptional and posttranscriptional gene expression. Cell Death and Differentiation (2017) 24, 785-797; doi:10.1038/cdd.2017.9; published online 10 February 2017EMT is a basic cellular process in which epithelial cells lose their epithelial characteristics and take on properties of mesenchymal cells. During EMT, epithelial cells lose their cell-cell junctions and the epithelial apical-basal polarity. The actin cytoskeleton is reorganized and cells acquire migratory and invasive properties.1-3 This process is essential in the generation of tissues and organs during embryogenesis, during wound healing and is associated with pathologies, such as fibrosis and cancer. In carcinomas, cancer cells can undergo EMT to escape the primary tumor, invade surrounding tissues and colonize remote sites via blood or lymphatic routes generating metastases. 4-6The EMT program can be activated efficiently and rapidly in epithelial cells in response to soluble factors or cytokines, including epidermal growth factor, fibroblast growth factors (FGFs) and transforming growth factors (TGF-βs). TGF-β may induce EMT through distinct signaling mechanisms causing substantial changes in gene expression. These changes involve three families of transcription factors: the zinc finger Snail, Zeb, and basic helix-loop-helix families. 7Beyond the well-established transcriptional reprogramming during EMT, posttranscriptional mechanisms, such as regulation by alternative pre-mRNA splicing and regulation by noncoding RNA, have an important role and provide an additional layer of complexity on the gene regulation during EMT. 8-12The mammalian genome encodes many thousands of lncRNAs, a class of transcripts 4200 nucleotides with limited protein-coding potential.13 They can act as molecular signals, tethers, decoys, guides or scaffolds at every level of gene regulation in a wide range of biological proc...

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“…67 lncRNAs influence gene expression by several pathways and are often associated with epigenetic regulation by silencing specific genes 68 and acting as chromatin modulators 69,70 and histone modificators. 52,71 lncRNAs can also alter gene expression through alternative splicing, 72 modulating the rates of RNA polymerase II initiation/elongation, 73 and forming paraspeckles structures. 74 In post-transcriptional levels, lncRNA can act in translation 75 and/or stability of target mRNAs 63 and as decoys for microRNAs, altering protein turnover.…”

Section: Long Noncoding Rnasmentioning

confidence: 99%

Long Noncoding RNAs in HPV-Induced Oncogenesis

Goedert¹,

Plaça²,

Nunes³

et al. 2016

Advances in Tumor Virology

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Long noncoding RNAs (lncRNAs) play important roles in a wide range of oncogenic processes, including malignant transformation, epigenetic reprogramming, epithelial-to-mesenchymal transition, and metastasis development. LncRNAs induced by oncogenic viral proteins were shown to play critical roles in tumor initiation and progression. Despite this, little is known about Human papillomavirus (HPV)-induced modulation of host's lncRNAs. In this review, we gathered published information about altered lncRNAs upon HPV status (infection/protein activity), making use of descriptive research works and published gene expression microarray experiments. A diversity of lncRNAs demonstrated to be altered, including metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), H19, and maternally expressed gene 3 (MEG3). Their functions in several cancers were reviewed, indicating that they may represent potential candidates for future research on HPV-induced oncogenesis.KEY WORDS: human papillomavirus, lncRNA, cancer, ncRNA, virus CITATION: goedert et al. long noncoding rnAs in HPv-induced oncogenesis.

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A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature

Cited by 234 publications

References 34 publications

ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia

ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia

Downregulation of Lnc-Spry1 mediates TGF-β-induced epithelial–mesenchymal transition by transcriptional and posttranscriptional regulatory mechanisms

Long Noncoding RNAs in HPV-Induced Oncogenesis

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