%0 Journal Article %1 Hovestadt2014 %A Hovestadt, Volker %A Jones, David T W. %A Picelli, Simone %A Wang, Wei %A Kool, Marcel %A Northcott, Paul A. %A Sultan, Marc %A Stachurski, Katharina %A Ryzhova, Marina %A Warnatz, Hans-Jörg %A Ralser, Meryem %A Brun, Sonja %A Bunt, Jens %A Jäger, Natalie %A Kleinheinz, Kortine %A Erkek, Serap %A Weber, Ursula D. %A Bartholomae, Cynthia C. %A von Kalle, Christof %A Lawerenz, Chris %A Eils, Jürgen %A Koster, Jan %A Versteeg, Rogier %A Milde, Till %A Witt, Olaf %A Schmidt, Sabine %A Wolf, Stephan %A Pietsch, Torsten %A Rutkowski, Stefan %A Scheurlen, Wolfram %A Taylor, Michael D. %A Brors, Benedikt %A Felsberg, Jörg %A Reifenberger, Guido %A Borkhardt, Arndt %A Lehrach, Hans %A Wechsler-Reya, Robert J. %A Eils, Roland %A Yaspo, Marie-Laure %A Landgraf, Pablo %A Korshunov, Andrey %A Zapatka, Marc %A Radlwimmer, Bernhard %A Pfister, Stefan M. %A Lichter, Peter %D 2014 %J Nature %K ABI-DKFZ %N 7506 %P 537--541 %R 10.1038/nature13268 %T Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. %U http://dx.doi.org/10.1038/nature13268 %V 510 %X Epigenetic 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.

@article{Hovestadt2014, __markedentry = {[bbrors:6]}, abstract = {Epigenetic 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.}, added-at = {2015-06-29T14:32:37.000+0200}, author = {Hovestadt, Volker and Jones, David T W. and Picelli, Simone and Wang, Wei and Kool, Marcel and Northcott, Paul A. and Sultan, Marc and Stachurski, Katharina and Ryzhova, Marina and Warnatz, Hans-J{\"{o}}rg and Ralser, Meryem and Brun, Sonja and Bunt, Jens and J{\"{a}}ger, Natalie and Kleinheinz, Kortine and Erkek, Serap and Weber, Ursula D. and Bartholomae, Cynthia C. and {von Kalle}, Christof and Lawerenz, Chris and Eils, J{\"{u}}rgen and Koster, Jan and Versteeg, Rogier and Milde, Till and Witt, Olaf and Schmidt, Sabine and Wolf, Stephan and Pietsch, Torsten and Rutkowski, Stefan and Scheurlen, Wolfram and Taylor, Michael D. and Brors, Benedikt and Felsberg, J{\"{o}}rg and Reifenberger, Guido and Borkhardt, Arndt and Lehrach, Hans and Wechsler-Reya, Robert J. and Eils, Roland and Yaspo, Marie-Laure and Landgraf, Pablo and Korshunov, Andrey and Zapatka, Marc and Radlwimmer, Bernhard and Pfister, Stefan M. and Lichter, Peter}, biburl = {https://www.bibsonomy.org/bibtex/22b90ff781ecff751829a3471d45c821f/juraeva}, doi = {10.1038/nature13268}, institution = { Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.}, interhash = {fb53a9a1b722fe36ab835fbc8219ce8b}, intrahash = {2b90ff781ecff751829a3471d45c821f}, journal = {Nature}, keywords = {ABI-DKFZ}, language = {eng}, medline-pst = {ppublish}, month = jun, number = 7506, owner = {bbrors}, pages = {537--541}, pii = {nature13268}, pmid = {24847876}, timestamp = {2015-06-29T14:34:20.000+0200}, title = {Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing.}, url = {http://dx.doi.org/10.1038/nature13268}, volume = 510, year = 2014 }