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000120695 0247_ $$2doi$$a10.1038/nature13268
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000120695 0247_ $$2ISSN$$a1476-4687
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000120695 1001_ $$0P:(DE-He78)744146d3b5a3df1e0ac555e5bf1ee5cc$$aHovestadt, Volker$$b0$$eFirst author$$udkfz
000120695 245__ $$aDecoding the regulatory landscape of medulloblastoma using DNA methylation sequencing.
000120695 260__ $$aLondon [u.a.]$$bNature Publ. Group$$c2014
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000120695 520__ $$aEpigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.
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000120695 650_7 $$2NLM Chemicals$$aChromatin
000120695 650_7 $$2NLM Chemicals$$aHistones
000120695 650_7 $$2NLM Chemicals$$aLIN28B protein, human
000120695 650_7 $$2NLM Chemicals$$aRNA-Binding Proteins
000120695 650_7 $$2NLM Chemicals$$aTranscription Factors
000120695 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b1$$udkfz
000120695 7001_ $$0P:(DE-HGF)0$$aPicelli, Simone$$b2
000120695 7001_ $$0P:(DE-He78)e19f7f8051b12f0faf7b251ef382263f$$aWang, Wei$$b3$$udkfz
000120695 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b4$$udkfz
000120695 7001_ $$0P:(DE-HGF)0$$aNorthcott, Paul A$$b5
000120695 7001_ $$aSultan, Marc$$b6
000120695 7001_ $$aStachurski, Katharina$$b7
000120695 7001_ $$aRyzhova, Marina$$b8
000120695 7001_ $$aWarnatz, Hans-Jörg$$b9
000120695 7001_ $$aRalser, Meryem$$b10
000120695 7001_ $$aBrun, Sonja$$b11
000120695 7001_ $$aBunt, Jens$$b12
000120695 7001_ $$0P:(DE-He78)bff9e3e3d86865d2b0836bb8f3ce98f3$$aJäger, Natalie$$b13$$udkfz
000120695 7001_ $$0P:(DE-He78)e053817bc90becc8a8dd8250e677e773$$aKleinheinz, Kortine$$b14$$udkfz
000120695 7001_ $$0P:(DE-He78)df8660bc5aba525f7fb6dba4aac15c1c$$aErkek, Serap$$b15$$udkfz
000120695 7001_ $$0P:(DE-He78)4fbd3823a23414f37b9f1a445cad566e$$aWeber, Ursula$$b16$$udkfz
000120695 7001_ $$0P:(DE-HGF)0$$aBartholomae, Cynthia C$$b17
000120695 7001_ $$0P:(DE-He78)5bacb661d5d7c0220d8f996d980ad8de$$avon Kalle, Christof$$b18$$udkfz
000120695 7001_ $$0P:(DE-He78)5398550c21bc4ce3b0ff670b04150334$$aLawerenz, Christian$$b19$$udkfz
000120695 7001_ $$0P:(DE-He78)442f4a5d2d41f01896229fac4d339d45$$aEils, Jürgen$$b20$$udkfz
000120695 7001_ $$aKoster, Jan$$b21
000120695 7001_ $$aVersteeg, Rogier$$b22
000120695 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b23$$udkfz
000120695 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b24$$udkfz
000120695 7001_ $$0P:(DE-He78)d6e2a991c1003a27b302b66a5477e6cd$$aSchmidt, Sabine$$b25$$udkfz
000120695 7001_ $$0P:(DE-He78)1efb774993effe7a66a6ffc1b1cf9ccb$$aWolf, Stephan$$b26$$udkfz
000120695 7001_ $$aPietsch, Torsten$$b27
000120695 7001_ $$aRutkowski, Stefan$$b28
000120695 7001_ $$aScheurlen, Wolfram$$b29
000120695 7001_ $$aTaylor, Michael D$$b30
000120695 7001_ $$0P:(DE-He78)fc949170377b58098e46141d95c72661$$aBrors, Benedikt$$b31$$udkfz
000120695 7001_ $$0P:(DE-HGF)0$$aFelsberg, Jörg$$b32
000120695 7001_ $$0P:(DE-HGF)0$$aReifenberger, Guido$$b33
000120695 7001_ $$0P:(DE-HGF)0$$aBorkhardt, Arndt$$b34
000120695 7001_ $$aLehrach, Hans$$b35
000120695 7001_ $$aWechsler-Reya, Robert J$$b36
000120695 7001_ $$0P:(DE-He78)78b6aa82148e60b4d91e3a37a6d3d9a0$$aEils, Roland$$b37$$udkfz
000120695 7001_ $$aYaspo, Marie-Laure$$b38
000120695 7001_ $$aLandgraf, Pablo$$b39
000120695 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b40$$udkfz
000120695 7001_ $$0P:(DE-He78)1beba8f953e7ae7e96e8d3e9a48f10f7$$aZapatka, Marc$$b41$$udkfz
000120695 7001_ $$0P:(DE-He78)d1939d434dd885fad08106329e3db719$$aRadlwimmer, Bernhard$$b42$$udkfz
000120695 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b43$$udkfz
000120695 7001_ $$0P:(DE-He78)e13b4363c5fe858044ef8a39c02c870c$$aLichter, Peter$$b44$$eLast author$$udkfz
000120695 773__ $$0PERI:(DE-600)1413423-8$$a10.1038/nature13268$$gVol. 510, no. 7506, p. 537 - 541$$n7506$$p537 - 541$$tNature <London>$$v510$$x1476-4687$$y2014
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