Human DNA methylomes at base resolution show widespread epigenomic differences

By Ryan Lister, Mattia Pelizzola, Robert H. Dowen, R. D. Hawkins, Gary Chung Hon, Julian Tonti-Filippini, Joseph R. Nery, Leonard K. Lee, Z. Ye, Queminh Ngo and 8 more. 2009

4,630 citations recorded by the source corpus.

DNA cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease. Here we present the first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA–protein interaction for several key regulatory factors. Widespread differences were identified in the composition and patterning of cytosine methylation between the two genomes. Nearly one-quarter of all methylation identified in embryonic stem cells was in a non-CG context, suggesting that embryonic stem cells may use different methylation mechanisms to affect gene regulation. Methylation in non-CG contexts showed enrichment in gene bodies and depletion in protein binding sites and enhancers. Non-CG methylation disappeared upon induced differentiation of the embryonic stem cells, and was restored in induced pluripotent stem cells. We identified hundreds of differentially methylated regions proximal to genes involved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblasts associated with lower transcriptional activity. These reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development.

Subfields: Molecular Biology

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Citations in the corpus

Impact of cytosine methylation on DNA binding specificities of human transcription factors (2017, background): “Gene bodies of highly expressed genes are heavily methylated (4, 5), whereas active gene regulatory elements have a low degree of methylation (6–8).”
Dnmt3a is essential for hematopoietic stem cell differentiation (2011, result): “Other studies have similarly observed a poor correlation in various human disease state”
DNA-binding factors shape the mouse methylome at distal regulatory regions (2011, background): “These dynamics can be explained directly by differential presence and activity of DNA-binding factors, highlighting that DNA methylation is more variable at LMRs than, for example, at CpG islands; (2) we provide evidence for REST and CTCF that LMR presence requires transcription factor binding; and ”
Epigenetic modifications and human disease (2010, background): “CHG and CHH methylation has been found in stem cells and seems to be enriched in gene bodies directly correlated with gene expression and to be depleted in protein binding sites and enhancer”
From RNA-seq reads to differential expression results (2010, background): “A few reports of these ‘integrative’ analyses have emerged recently [71-73].”
Dynamic DNA methylation across diverse human cell lines and tissues (2013, background): “The corepressor CTBP2 was also enriched at these sites and sig- Genome Research 557 www.genome.org nificantly overlapped SUZ12-bound loci in ESCs (Fisher’s exact test, BH-adjusted, P = 9.75 3 10 20).”
Direct detection of DNA methylation during single-molecule, real-time sequencing (2010, background): “Abundant cytosine methylation in non–C-G contexts has been recently found in human embryonic stem cells but not in differentiated cells, suggesting that it is a distinct type of methylation involved in the maintenance of the pluripotent stat”
The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells (2012, neutral): “5 postimplantation embryo (Hajkova et al., 2002; Lister et al., 2009; Laurent et al., 2010; Stadler et al., 2011; Smith et al., 2012) (Figure 1A).”
Pervasive Transcription of the Human Genome Produces Thousands of Previously Unidentified Long Intergenic Noncoding RNAs (2013, methodology): “RNA-seq data from IMR90 cells [29] was also analyzed to obtain FPKM values for lincRNAs and RefSeq NM genes using the same procedure used for lincRNA discovery.”
The Honey Bee Epigenomes: Differential Methylation of Brain DNA in Queens and Workers (2010, background): “Finally, the number of methylated cytosines in Apis is nearly three orders of magnitude lower than in the human genome [11].”
A review on machine learning principles for multi-view biological data integration (2016, background): “…human genome; DNase-seq [8] detects open chromatin regions for transcription factor binding loci (epige-nomic level); whole genome bisulfite-seq [9] allows to build methylomes which are key to understand gene regulation, X chromosome inactivation and cancerogenesis (epigenetic level); RNA-seq…”
Epigenetic regulation of neurogenesis in the adult mammalian brain (2011, background): “Limited non-CpG methylation has been found in embryonic stem cells (Ramsahoye et al., 2000; Lister et al., 2009), but has not yet been characterized in detail in other cell types, such as neural progenitors and their progeny.”
Editing DNA methylation in the mammalian genome (2016, neutral): “Owing to the advancement in sequencing technologies, single-nucleotide resolution methylation maps for many types of human and mouse cells and tissues have been depicted (Lister et al., 2009, 2013).”