title: Genomic distribution and inter-sample variation of non-CpG methylation across human cell types.
abstract: DNA methylation plays an important role in development and disease. The primary sites of DNA methylation in vertebrates are cytosines in the CpG dinucleotide context, which account for roughly three quarters of the total DNA methylation content in human and mouse cells. While the genomic distribution, inter-individual stability, and functional role of CpG methylation are reasonably well understood, little is known about DNA methylation targeting CpA, CpT, and CpC (non-CpG) dinucleotides. Here we report a comprehensive analysis of non-CpG methylation in 76 genome-scale DNA methylation maps across pluripotent and differentiated human cell types. We confirm non-CpG methylation to be predominantly present in pluripotent cell types and observe a decrease upon differentiation and near complete absence in various somatic cell types. Although no function has been assigned to it in pluripotency, our data highlight that non-CpG methylation patterns reappear upon iPS cell reprogramming. Intriguingly, the patterns are highly variable and show little conservation between different pluripotent cell lines. We find a strong correlation of non-CpG methylation and DNMT3 expression levels while showing statistical independence of non-CpG methylation from pluripotency associated gene expression. In line with these findings, we show that knockdown of DNMTA and DNMT3B in hESCs results in a global reduction of non-CpG methylation. Finally, non-CpG methylation appears to be spatially correlated with CpG methylation. In summary these results contribute further to our understanding of cytosine methylation patterns in human cells using a large representative sample set.
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ziller
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.forename: Jing
authors.initials: J
authors.lastname: Liao
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hongcang
authors.initials: H
authors.lastname: Gu
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
authors.forename: Patrick
authors.initials: P
authors.lastname: Boyle
authors.forename: Charles B
authors.initials: CB
authors.lastname: Epstein
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.forename: Andreas
authors.initials: A
authors.lastname: Gnirke
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D018899:CpG Islands / Q000235:genetics*; D003596:Cytosine / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D053595:Embryonic Stem Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D015894:Genome, Human; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D051379:Mice; D039904:Pluripotent Stem Cells / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000097584:DNA Methyltransferase 3B
chemical_list: D003596:Cytosine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D034741:RNA, Small Interfering; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human