title: Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer.
abstract: Bivalent (poised or paused) chromatin comprises activating and repressing histone modifications at the same location. This combination of epigenetic marks at promoter or enhancer regions keeps genes expressed at low levels but poised for rapid activation. Typically, DNA at bivalent promoters is only lowly methylated in normal cells, but frequently shows elevated methylation levels in cancer samples. Here, we developed a universal classifier built from chromatin data that can identify cancer samples solely from hypermethylation of bivalent chromatin. Tested on over 7,000 DNA methylation data sets from several cancer types, it reaches an AUC of 0.92. Although higher levels of DNA methylation are often associated with transcriptional silencing, counter-intuitive positive statistical dependencies between DNA methylation and expression levels have been recently reported for two cancer types. Here, we re-analyze combined expression and DNA methylation data sets, comprising over 5,000 samples, and demonstrate that the conjunction of hypermethylation of bivalent chromatin and up-regulation of the corresponding genes is a general phenomenon in cancer. This up-regulation affects many developmental genes and transcription factors, including dozens of homeobox genes and other genes implicated in cancer. Thus, we reason that the disturbance of bivalent chromatin may be intimately linked to tumorigenesis.
authors.affiliation: Leipzig University, Chair of Bioinformatics, Leipzig, 04107, Germany.|Leipzig University, Transcriptome Bioinformatics Group - Interdisciplinary Center for Bioinformatics, Leipzig, 04107, Germany.
authors.forename: Stephan H
authors.initials: SH
authors.lastname: Bernhart
authors.affiliation: Leipzig University, Chair of Bioinformatics, Leipzig, 04107, Germany.|Leipzig University, Transcriptome Bioinformatics Group - Interdisciplinary Center for Bioinformatics, Leipzig, 04107, Germany.
authors.forename: Helene
authors.initials: H
authors.lastname: Kretzmer
authors.affiliation: Ludwig-Maximilians-University, Institute of Laboratory Medicine, Munich, 81377, Germany.
authors.forename: Lesca M
authors.initials: LM
authors.lastname: Holdt
authors.affiliation: Leipzig University, Chair of Bioinformatics, Leipzig, 04107, Germany.|Leipzig University, Transcriptome Bioinformatics Group - Interdisciplinary Center for Bioinformatics, Leipzig, 04107, Germany.|Inserm, U1110 - Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, 67000, France.|Université de Strasbourg, Strasbourg, 67000, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Jühling
authors.affiliation: Christian Albrechts University &University Hospital Schleswig-Holstein - Campus Kiel, Institute of Human Genetics, Kiel, 24105, Germany.
authors.forename: Ole
authors.initials: O
authors.lastname: Ammerpohl
authors.affiliation: Christian Albrechts University &University Hospital Schleswig-Holstein - Campus Kiel, Institute of Human Genetics, Kiel, 24105, Germany.|Christian Albrechts University Kiel &University Hospital Schleswig-Holstein - Campus Kiel, Department of Pediatrics, Kiel, 24105, Germany.
authors.forename: Anke K
authors.initials: AK
authors.lastname: Bergmann
authors.affiliation: Ludwig-Maximilians-University, Institute of Laboratory Medicine, Munich, 81377, Germany.
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Northoff
authors.affiliation: Leipzig University, Chair of Bioinformatics, Leipzig, 04107, Germany.|Leipzig University, Transcriptome Bioinformatics Group - Interdisciplinary Center for Bioinformatics, Leipzig, 04107, Germany.
authors.forename: Gero
authors.initials: G
authors.lastname: Doose
authors.affiliation: Christian Albrechts University &University Hospital Schleswig-Holstein - Campus Kiel, Institute of Human Genetics, Kiel, 24105, Germany.|Ulm University &Ulm University Medical Center, Institute for Human Genetics, Ulm, 89081, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Leipzig University, Chair of Bioinformatics, Leipzig, 04107, Germany.|Leipzig University, Transcriptome Bioinformatics Group - Interdisciplinary Center for Bioinformatics, Leipzig, 04107, Germany.|Leipzig University, LIFE - Leipzig Research Center for Civilization Diseases, Leipzig, 04107, Germany.|University of Vienna, Department of Theoretical Chemistry, Vienna, 1090, Austria.|Max-Planck-Institute for Mathematics in Sciences, Leipzig, 04103, Germany.|Santa Fe Institute, Santa Fe, NM 87501, USA.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Stadler
authors.affiliation: Leipzig University, Chair of Bioinformatics, Leipzig, 04107, Germany.|Leipzig University, Transcriptome Bioinformatics Group - Interdisciplinary Center for Bioinformatics, Leipzig, 04107, Germany.|Leipzig University, LIFE - Leipzig Research Center for Civilization Diseases, Leipzig, 04107, Germany.
authors.forename: Steve
authors.initials: S
authors.lastname: Hoffmann
mesh_terms: D002843:Chromatin / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D050437:Genes, Developmental / Q000235:genetics*; D042421:Histone Code / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics
chemical_list: D002843:Chromatin; D009363:Neoplasm Proteins; D014157:Transcription Factors