title: Computational analysis of genome-wide DNA methylation during the differentiation of human embryonic stem cells along the endodermal lineage.
abstract: The generation of genome-wide data derived from methylated DNA immunoprecipitation followed by sequencing (MeDIP-seq) has become a major tool for epigenetic studies in health and disease. The computational analysis of such data, however, still falls short on accuracy, sensitivity, and speed. We propose a time-efficient statistical method that is able to cope with the inherent complexity of MeDIP-seq data with similar performance compared with existing methods. In order to demonstrate the computational approach, we have analyzed alterations in DNA methylation during the differentiation of human embryonic stem cells (hESCs) to definitive endoderm. We show improved correlation of normalized MeDIP-seq data in comparison to available whole-genome bisulfite sequencing data, and investigated the effect of differential methylation on gene expression. Furthermore, we analyzed the interplay between DNA methylation, histone modifications, and transcription factor binding and show that in contrast to de novo methylation, demethylation is mainly associated with regions of low CpG densities.
authors.affiliation: Department of Vertebrate Genomics, Max-Planck-Institute for Molecular Genetics, D-14195 Berlin, Germany. chavez@molgen.mpg.de
authors.forename: Lukas
authors.initials: L
authors.lastname: Chavez
authors.forename: Justyna
authors.initials: J
authors.lastname: Jozefczuk
authors.forename: Christina
authors.initials: C
authors.lastname: Grimm
authors.forename: Jörn
authors.initials: J
authors.lastname: Dietrich
authors.forename: Bernd
authors.initials: B
authors.lastname: Timmermann
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.forename: Ralf
authors.initials: R
authors.lastname: Herwig
authors.forename: James
authors.initials: J
authors.lastname: Adjaye
mesh_terms: D002454:Cell Differentiation; D019295:Computational Biology / Q000379:methods*; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004707:Endoderm / Q000378:metabolism*; D057890:Epigenomics; D015870:Gene Expression; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D047468:Immunoprecipitation; D017422:Sequence Analysis, DNA; D012984:Software
references.citation: Genome Res. 2004 May;14(5):925-8
references.pmid: 15078858
references.citation: Nat Rev Genet. 2010 Mar;11(3):191-203
references.pmid: 20125086
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D61-5
references.pmid: 17130148
references.citation: Nat Genet. 2005 Aug;37(8):853-62
references.pmid: 16007088
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3740-5
references.pmid: 11891299
references.citation: Nat Genet. 2009 Feb;41(2):178-186
references.pmid: 19151715
references.citation: Bioinformatics. 2004 Dec 12;20(18):3705-6
references.pmid: 15297296
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D613-9
references.pmid: 19906737
references.citation: Nat Biotechnol. 2005 Dec;23(12):1534-41
references.pmid: 16258519
references.citation: Nature. 2009 Nov 19;462(7271):315-22
references.pmid: 19829295
references.citation: Genome Res. 2008 Sep;18(9):1518-29
references.pmid: 18577705
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D755-61
references.pmid: 18996895
references.citation: Genome Biol. 2009 Feb 10;10(2):R14
references.pmid: 19208250
references.citation: Genome Res. 2009 Jun;19(6):1044-56
references.pmid: 19273619
references.citation: Genome Res. 2008 Oct;18(10):1652-9
references.pmid: 18765822
references.citation: Nature. 2008 Aug 7;454(7205):766-70
references.pmid: 18600261
references.citation: Cell. 2008 May 2;133(3):523-36
references.pmid: 18423832
references.citation: Cell. 2007 Feb 23;128(4):683-92
references.pmid: 17320506
references.citation: Nat Biotechnol. 2009 Apr;27(4):353-60
references.pmid: 19330000
references.citation: Nat Biotechnol. 2009 Nov;27(11):1033-7
references.pmid: 19826408
references.citation: J Cell Biochem. 2010 Jan 1;109(1):1-6
references.pmid: 19899110
references.citation: Genome Biol. 2004;5(10):R80
references.pmid: 15461798
references.citation: BMC Genomics. 2009 Jul 15;10:314
references.pmid: 19604364
references.citation: Cell. 2007 May 18;129(4):823-37
references.pmid: 17512414
references.citation: Genome Res. 2009 Aug;19(8):1462-70
references.pmid: 19491193
references.citation: Bioinformatics. 2007 Aug 15;23(16):2183-4
references.pmid: 17586828
references.citation: Genome Res. 2008 Nov;18(11):1851-8
references.pmid: 18714091
references.citation: Stem Cells. 2008 May;26(5):1117-27
references.pmid: 18292207
references.citation: J Mol Biol. 1987 Jul 20;196(2):261-82
references.pmid: 3656447
references.citation: Nat Biotechnol. 2008 Jul;26(7):779-85
references.pmid: 18612301
references.citation: Nucleic Acids Res. 2009 Oct;37(18):e123
references.pmid: 19620212
references.citation: Nat Genet. 2006 Dec;38(12):1378-85
references.pmid: 17072317