Dynamic changes in the human methylome during differentiation.

By L. Laurent, Eleanor Wong, Guoliang Li, Tien Huynh, Aristotelis Tsirigos, C. T. Ong, Hwee Meng Low, Ken Wing Kin Sung, Isidore Rigoutsos, J. Loring and 1 more. Genome Research, 2010

1,065 citations recorded by the source corpus.

DNA methylation is a critical epigenetic regulator in mammalian development. Here, we present a whole-genome comparative view of DNA methylation using bisulfite sequencing of three cultured cell types representing progressive stages of differentiation: human embryonic stem cells (hESCs), a fibroblastic differentiated derivative of the hESCs, and neonatal fibroblasts. As a reference, we compared our maps with a methylome map of a fully differentiated adult cell type, mature peripheral blood mononuclear cells (monocytes). We observed many notable common and cell-type-specific features among all cell types. Promoter hypomethylation (both CG and CA) and higher levels of gene body methylation were positively correlated with transcription in all cell types. Exons were more highly methylated than introns, and sharp transitions of methylation occurred at exon-intron boundaries, suggesting a role for differential methylation in transcript splicing. Developmental stage was reflected in both the level of global methylation and extent of non-CpG methylation, with hESC highest, fibroblasts intermediate, and monocytes lowest. Differentiation-associated differential methylation profiles were observed for developmentally regulated genes, including the HOX clusters, other homeobox transcription factors, and pluripotence-associated genes such as POU5F1, TCF3, and KLF4. Our results highlight the value of high-resolution methylation maps, in conjunction with other systems-level analyses, for investigation of previously undetectable developmental regulatory mechanisms.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3e3fbd588b1deebdf12c298cf6526a7e5d1a2e60

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In Molecular Biology

1. Wolf Reik
2. Hao Wu
3. Christoph Bock
4. Kasper D. Hansen
5. W. Dean
6. Jörn Walter
7. Yi Zhang
8. Alexander Meissner

Citations in the corpus

• R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters (2012, positive): “Analysis of humanmethylome data (Laurent et al., 2010) revealed that highly skewed CGIs showed the most significant reduction of DNA methylation around the TSS, both in terms of absolute levels and size of protected region (Figure 6D).”
• De novo identification of differentially methylated regions in the human genome (2015, background): “Background DNA methylation is widely regarded as the most stable epigenetic mark and, for explaining patterns of gene expression, cell differentiation and phenotype, one of the most informative [1-3].”
• Preparation of reduced representation bisulfite sequencing libraries for genome-scale DNA methylation profiling (2011, background): “Genome-scale studies have refined this simple view and shown that the effect is largely dependent on the genomic locatio”
• A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue (2013, positive): “supported by multiple studies showing a positive correlation between gene body methylation and active transcription [40], and that DNA methylation may regulate exon splicing [41,42].”
• The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells (2012, positive): “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).”
• Dynamic DNA methylation across diverse human cell lines and tissues (2013, background): “2008) and even whole human genomes (Cokus et al. 2008; Lister et al. 2009; Laurent et al. 2010; Li et al. 2010; Hansen et al. 2011; Berman et al. 2012; Hon et al. 2012).”
• Epigenetic modifications and human disease (2010, background): “The levels of non-CpG methylation decrease during differentiation and are restored in induced pluripotent stem cells, suggesting a key role in origin and maintenance of pluripotent stat”
• Complexity of the Alternative Splicing Landscape in Plants[C][W][OPEN] (2013, background): “Further, exon–intron boundaries showed sharp transitions in methylation (Chodavarapu et al., 2010; Laurent et al., 2010).”
• Neuronal activity modifies DNA methylation landscape in the adult brain (2011, neutral): “5b ), which is also similar to findings from the human methylom”
• Spontaneous epigenetic variation in the Arabidopsis thaliana methylome (2011, background): “Because exon-specific methylation may influence RNA splicing pattern”