FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2291613414> ?p ?o ?g. }

• W2291613414 endingPage "560" @default.
• W2291613414 startingPage "558" @default.
• W2291613414 abstract "News & Views18 February 2016free access The cis-regulatory switchboard of pancreatic ductal cancer Jorge Ferrer Jorge Ferrer [email protected] Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London, UK Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain Search for more papers by this author Francisco X Real Francisco X Real [email protected] Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid, Spain Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain Search for more papers by this author Jorge Ferrer Jorge Ferrer [email protected] Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London, UK Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain Search for more papers by this author Francisco X Real Francisco X Real [email protected] Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid, Spain Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain Search for more papers by this author Author Information Jorge Ferrer1,2 and Francisco X Real3,4 1Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London, UK 2Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain 3Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid, Spain 4Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain The EMBO Journal (2016)35:558-560https://doi.org/10.15252/embj.201693999 See also: GR Diaferia et al (March 2016) PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating human diseases. There is consequently a pressing need to understand its molecular underpinnings, which should enable new preventive and therapeutic strategies. A new study in The EMBO Journal (Diaferia et al, 2016) maps the transcriptome and epigenetic landscape associated with distinct PDAC grades and identifies cis- and trans-regulatory elements in tumour progression. PDAC originally acquired its name from its histological similarity with normal pancreatic ducts. However, recent work has shown that tumours with ductal morphology can arise upon activation of mutant Kras in duct-like embryonic pancreatic progenitors or in pancreatic acinar cells through a process known as acino-ductal metaplasia (Tuveson et al, 2004; Guerra et al, 2007; Pérez-Mancera et al, 2012). Acino-ductal metaplasia has thus been proposed to involve a process where acinar cells are reprogrammed to an embryonic duct cell progenitor state (Rooman & Real, 2012; Roy & Hebrok, 2015). PDAC tumours of low or moderate histological grade retain ductal features, while this phenotype is not seen in more aggressive high-grade tumours. The profound changes in cellular phenotypes that take place throughout pancreatic carcinogenesis are likely triggered by both somatic genetic alterations in tumour cells and environmental cues such as stromal-derived signals, but they need to be executed by cell-specific transcriptional programmes. This means that there should be specific transcription factors that control regulatory programmes in each histological phenotype. On the other hand, it is now known that transcription factors control cell-specific programmes through the activation of tens of thousands of transcriptional regulatory elements, including long-range enhancers and proximal promoters, which in turn activate specific cohorts of cell-specific genes. Despite recent progress in understanding the epigenome of human embryonic pancreatic progenitors (Cebola et al, 2015), so far no study has systematically tackled the transcription factor and enhancer networks that underpin ductal differentiation in normal and tumour cells. Gioacchino Natoli and colleagues have now examined the regulatory landscape of low- and high-grade human PDAC cell lines (Diaferia et al, 2016). They generated genomewide maps of active transcripts, enhancers and promoters in these cells and found that such regulatory features showed a striking clustering with histological grade (Fig 1). They identified sets of transcription factors that are selectively expressed in low-grade PDAC, including IRF1, ELF3, FOXA1, KLF5 and HNF1B, a core marker of embryonic and adult ducts. They also defined transcription factors that were selectively expressed in high-grade PDAC, such as ZEB1, IRF1, GATA2, ETV5 and TCF12. In parallel, they interrogated genomic sequences that are selectively used as transcriptional enhancers in low-grade PDAC and found these to be highly enriched in recognition sequences for transcription factors that were found to be selectively expressed in PDAC. This finding was further corroborated by experimental analysis of genomewide binding of five of these factors. The analysis thus uncovered a core set of enhancer clusters that were specific for low-grade PDAC, several of which map to putative stage-specific regulatory genes, including KLF5. Importantly, the authors found that the transcriptional phenotype associated with stage-specific programmes could be largely explained by the activation of grade-specific enhancers. Figure 1. Genomewide regulatory maps identified distinct enhancers that are active in low-grade versus high-grade PDACKLF5 plays a key role in the activation of low-grade PDAC enhancers, which activates epithelial transcriptional programmes, and suppresses ZEB1, a regulator of the high-grade mesenchymal PDAC transcriptional programme, which in turn suppresses the low-grade epithelial programme. Download figure Download PowerPoint Natoli and colleagues next tested the functional role of grade-specific transcription factors in PDAC. They used CRISPR-Cas9 to inactivate KLF5 and ELF3 in a low-grade PDAC cell line. The consequences of knocking out ELF3 were comparatively mild, but inactivation of KLF5 caused a dramatic epigenomic phenotype, with a reduction in H3K27ac and H3K4me levels (characteristic marks of active enhancers) in more than 20% of PDAC enhancers. Many of the affected enhancers were directly bound by KLF5 in wt cells, and in KLF5 knockout cells, they showed decreased binding of other transcription factors such as ELF3 and FOXA1. This suggests that KLF5 binding is required to nucleate the recruitment of transcription factors and to activate a large set of low-grade PDAC enhancers. KLF5-dependent enhancers were often located near genes that regulate proliferation and epithelial cell identity genes, and many such genes showed decreased expression in knockout cells. However, the authors also identified sub-programmes of epithelial identity that were only indirectly dependent on KLF5. In KLF5 knockout cells, markers of epithelial–mesenchymal transition, such as vimentin and the transcriptional repressor ZEB1, were increased, and overexpression of ZEB1 partially recapitulated the changes observed in the KLF5 knockouts. Not surprisingly, xenografts of KLF5 knockout cells acquired a mesenchymal, rather than epithelial, cell morphology. These studies therefore delineated how the coordinated action of specific transcriptional regulators controls the enhancer programme that defines the phenotype of low-grade PDAC cells. More generally, these elegant studies illustrate the power of combining epigenomics and genome editing to define critical programming events in cancer. They clearly pave the way to further studies of this nature in other tumour models, such as primary organoids (Boj et al, 2015), or in heterotypic systems (i.e. including inflammatory or stromal cells) to more precisely define transcriptional programming mechanisms that underlie the initiation of pancreatic carcinogenesis, or to define more clearly the exact transcriptional mechanisms that underlie specific PDAC subtypes. The notion that deranged transcriptional programmes are central for carcinogenesis is supported by the observation that genes encoding chromatin regulatory proteins are frequently mutated in human cancers, including PDAC (Waddell et al, 2015). Interestingly, several transcriptional activators identified as regulators of the PDAC enhancer programme are mutated in other epithelial cancers (e.g. ELF3 and KLF5 in urothelial bladder cancer) (Cancer Genome Atlas Research Network, 2014) although somatic defects in these genes have so far not been reported in PDAC (Waddell et al, 2015). The importance of transcriptional programming mechanisms in pancreatic cancer is also in keeping with recent work showing that, in mice, PDAC can be treated with small-molecule inhibitors of proteins that interact with acetylated or methylated nucleosomal histones (Mazur et al, 2015). Moreover, chromatin regulators have been shown to affect pancreatic tumour initiation or progression (von Figura et al, 2014; Richart et al, 2016). It is thus reasonable to foresee that a more detailed understanding of the transcription factor and enhancer networks that control discrete stages of PDAC will provide further opportunities to develop precision therapies. The maps of active regulatory elements in low- and high-grade PDAC are also relevant to efforts to decipher the mutational landscape of PDAC. The analysis of tumour exomes has uncovered multiple genes that are enriched in somatic mutations in PDAC, several of which are drivers of cancer initiation or progression. More recent efforts, such as Genome England's 100,000 genomes project, aim to interrogate whole-genome sequences in human tumours. Deciphering which non-coding mutations might be relevant to PDAC pathogenesis is a formidable challenge that requires a priori knowledge of which non-coding sequences are potentially relevant to this disease. The availability of PDAC regulatory maps should provide an opportunity to test the hypothesis that mutations in specific regulatory elements contribute to PDAC through dysregulation of transcription. The pioneering work from Natoli and colleagues (Diaferia et al, 2016) therefore opens diverse avenues to further our understanding of the pathogenesis and treatment of pancreatic cancer. References Boj SF, Hwang CI, Baker LA, Chio II, Engle DD, Corbo V, Jager M, Ponz-Sarvise M, Tiriac H, Spector MS, Gracanin A, Oni T, Yu KH, van Boxtel R, Huch M, Rivera KD, Wilson JP, Feigin ME, Öhlund D, Handly-Santana A et al (2015) Organoid models of human and mouse ductal pancreatic cancer. Cell 160: 324–338CrossrefCASPubMedWeb of Science®Google Scholar Cancer Genome Atlas Research (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507: 315–322CrossrefCASPubMedWeb of Science®Google Scholar Cebola I, Rodríguez-Seguí SA, Cho CH, Bessa J, Rovira M, Luengo M, Chhatriwala M, Berry A, Ponsa-Cobas J, Maestro MA, Jennings RE, Pasquali L, Morán I, Castro N, Hanley NA, Gomez-Skarmeta JL, Vallier L, Ferrer J (2015) TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors. Nat Cell Biol 17: 615–626CrossrefCASPubMedWeb of Science®Google Scholar Diaferia GR, Balestrieri C, Prosperini E, Nicoli P, Spaggiari P, Zerbi A, Natoli G (2016) Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer. EMBO J 35: 595–617Wiley Online LibraryCASPubMedWeb of Science®Google Scholar von Figura G, Fukuda A, Roy N, Liku ME, Morris Iv JP, Kim GE, Russ HA, Firpo MA, Mulvihill SJ, Dawson DW, Ferrer J, Mueller WF, Busch A, Hertel KJ, Hebrok M (2014) The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nat Cell Biol 16: 255–267CrossrefCASPubMedWeb of Science®Google Scholar Guerra C, Schuhmacher AJ, Cañamero M, Grippo PJ, Verdaguer L, Pérez-Gallego L, Dubus P, Sandgren EP, Barbacid M (2007) Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11: 291–302CrossrefCASPubMedWeb of Science®Google Scholar Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sánchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noël PB, Braren R, Erkan M, Kleeff J, Sipos B, Sayles LC, Heikenwalder M et al (2015) Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med 21: 1163–1171CrossrefCASPubMedWeb of Science®Google Scholar Pérez-Mancera PA, Guerra C, Barbacid M, Tuveson DA (2012) What we have learned about pancreatic cancer from mouse models. Gastroenterology 142: 1079–1092CrossrefPubMedWeb of Science®Google Scholar Richart L, Carrillo-de Santa Pau E, Rio-Machin A, Pérez de Andrés M, Cigudosa JC, Sanchez-Arevalo Lobo VJ, Real FX (2016) Bptf is required for c-Myc transcriptional activity and in vivo tumorigenesis. Nat Comm 7: 10153CrossrefCASPubMedWeb of Science®Google Scholar Rooman I, Real FX (2012) Pancreatic ductal adenocarcinoma and acinar cells: a matter of differentiation and development? Gut 61: 449–458CrossrefPubMedWeb of Science®Google Scholar Roy N, Hebrok M (2015) Regulation of cellular identity in cancer. Dev Cell 21: 674–684CrossrefCASWeb of Science®Google Scholar Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S, Mercer KL, Grochow R, Hock H, Crowley D, Hingorani SR, Zaks T, King C, Jacobetz MA, Wang L, Bronson RT, Orkin SH, DePinho RA, Jacks T (2004) Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5: 375–387CrossrefCASPubMedWeb of Science®Google Scholar Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, Quinn MC, Robertson AJ, Fadlullah MZ, Bruxner TJ, Christ AN, Harliwong I, Idrisoglu S, Manning S, Nourse C, Nourbakhsh E et al (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518: 495–501CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 35,Issue 6,15 March 2016Cover: In the absence of thrombopoietin (TPO), tyrosine‐unphosphorylated STAT5 (uSTAT5) is present in the nucleus where it colocalises with CTCF and represses a megakaryocytic transcriptional program. TPO‐mediated phosphorylation of STAT5 triggers its genome‐wide relocation to STAT consensus sites with two distinct transcriptional consequences; loss of a uSTAT5 program which restrains megakaryocytic differentiation and activation of a canonical pSTAT5‐driven program which includes regulators of apoptosis and proliferation. Transcriptional repression by uSTAT5 reflects, in part, restricted access of the megakaryocytic transcription factor ERG to target genes. From Hyun Jung Park, Berthold Göttgens, Anthony R Green and colleagues: Cytokine-induced megakaryocytic differentiation is regulated by genome-wide loss of a uSTAT transcriptional program. For details, see the Article on p 580, also highlighted by Decker on p 555. Concept and images by Hyun Jung Park (Artistic rendition by Uta Mackensen) Volume 35Issue 615 March 2016In this issue FiguresReferencesRelatedDetailsLoading ..." @default.
• W2291613414 created "2016-06-24" @default.
• W2291613414 creator A5058666146 @default.
• W2291613414 creator A5082200538 @default.
• W2291613414 date "2016-02-18" @default.
• W2291613414 modified "2023-10-16" @default.
• W2291613414 title "The <i>cis</i> ‐regulatory switchboard of pancreatic ductal cancer" @default.
• W2291613414 cites W1939365747 @default.
• W2291613414 cites W1970847274 @default.
• W2291613414 cites W1987313243 @default.
• W2291613414 cites W2010916968 @default.
• W2291613414 cites W2045356233 @default.
• W2291613414 cites W2050389860 @default.
• W2291613414 cites W2056646351 @default.
• W2291613414 cites W2068523052 @default.
• W2291613414 cites W2081528800 @default.
• W2291613414 cites W2124088238 @default.
• W2291613414 cites W2217105140 @default.
• W2291613414 cites W2252980137 @default.
• W2291613414 cites W2268945528 @default.
• W2291613414 doi "https://doi.org/10.15252/embj.201693999" @default.
• W2291613414 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4801950" @default.
• W2291613414 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26893390" @default.
• W2291613414 hasPublicationYear "2016" @default.
• W2291613414 type Work @default.
• W2291613414 sameAs 2291613414 @default.
• W2291613414 citedByCount "1" @default.
• W2291613414 countsByYear W22916134142021 @default.
• W2291613414 crossrefType "journal-article" @default.
• W2291613414 hasAuthorship W2291613414A5058666146 @default.
• W2291613414 hasAuthorship W2291613414A5082200538 @default.
• W2291613414 hasBestOaLocation W22916134142 @default.
• W2291613414 hasConcept C121608353 @default.
• W2291613414 hasConcept C126322002 @default.
• W2291613414 hasConcept C2780210213 @default.
• W2291613414 hasConcept C502942594 @default.
• W2291613414 hasConcept C54355233 @default.
• W2291613414 hasConcept C70721500 @default.
• W2291613414 hasConcept C71924100 @default.
• W2291613414 hasConcept C86803240 @default.
• W2291613414 hasConceptScore W2291613414C121608353 @default.
• W2291613414 hasConceptScore W2291613414C126322002 @default.
• W2291613414 hasConceptScore W2291613414C2780210213 @default.
• W2291613414 hasConceptScore W2291613414C502942594 @default.
• W2291613414 hasConceptScore W2291613414C54355233 @default.
• W2291613414 hasConceptScore W2291613414C70721500 @default.
• W2291613414 hasConceptScore W2291613414C71924100 @default.
• W2291613414 hasConceptScore W2291613414C86803240 @default.
• W2291613414 hasIssue "6" @default.
• W2291613414 hasLocation W22916134141 @default.
• W2291613414 hasLocation W22916134142 @default.
• W2291613414 hasLocation W22916134143 @default.
• W2291613414 hasLocation W22916134144 @default.
• W2291613414 hasOpenAccess W2291613414 @default.
• W2291613414 hasPrimaryLocation W22916134141 @default.
• W2291613414 hasRelatedWork W2043890160 @default.
• W2291613414 hasRelatedWork W2337729630 @default.
• W2291613414 hasRelatedWork W2401514044 @default.
• W2291613414 hasRelatedWork W2752933131 @default.
• W2291613414 hasRelatedWork W2764038087 @default.
• W2291613414 hasRelatedWork W3013358603 @default.
• W2291613414 hasRelatedWork W3080409807 @default.
• W2291613414 hasRelatedWork W3103168443 @default.
• W2291613414 hasRelatedWork W3104966608 @default.
• W2291613414 hasRelatedWork W35632224 @default.
• W2291613414 hasVolume "35" @default.
• W2291613414 isParatext "false" @default.
• W2291613414 isRetracted "false" @default.
• W2291613414 magId "2291613414" @default.
• W2291613414 workType "article" @default.