DNA Methylation Profile: A Composer-, Conductor-, and Player-Orchestrated Mammalian Genome Consisting of Genes and Transposable Genetic Elements

Abstract

Abstract. Epigenetic systems play crucial roles in the differentiation of a mammalian fertilized egg into hundreds of cell types exhibiting distinct phenotypes, using a set of DNA molecules comprising about 3 billion nucleotides. Genomewide analyses of epigenetic marks have revealed the remarkably well-established and well-maintained structure of the epigenome, consisting of DNA methylation and histone modifications that vary their state in a tissue type-and developmental stage-specific manner at numerous genomic loci. DNA methylation profiles comprising numerous tissuedependent and differentially methylated regions (T-DMRs), found at such loci, are unique to every type of cell and tissue, and illuminate molecular networks that represent their phenotypes. T-DMRs are located in not only genic but also nongenic regions-including transposable genetic elements, such as short interspersed transposable element. Epigenetic studies indicate that the molecules that perform these modifications directly, such as DNA methyltransferases and eukaryotic histone methyltransferases, or indirectly, such as CpG-binding protein and noncoding RNAs-and combinations of these-contribute to the DNA methylation profile. It remains to be addressed how these molecules precisely find their target genomic loci. Key words: CpG island, DNA methylation profile, Methylome, Tissue-dependent and differently methylated region (T-DMR) (J. Reprod. Dev. 58: [265][266][267][268][269][270][271][272][273] 2012) T he mammalian body consists of about 200 types of cells, which can be discriminated from each other by their phenotype. All cells are descendants of a single fertilized egg. During development, cells change their phenotypes and their fates by responding to extrinsic and intrinsic signals using appropriate, but distinct, sets of genes without changing the genome sequence. Sets of transcription factors are the major players that govern the cell type-and tissue-specific use of the genome. Recent studies indicate that expression of these key players is under the control of another mechanism [1, 2]-the epigenetic system-that enables cells to exhibit their stable cell type-specific phenotypes over multiple generations. The epigenetic system, therefore, is considered a memory for genome use that defines cell types and tissues.The epigenome is the genome-wide combination of DNA methylation, histone modifications, and chromatin architecture. Recent advances in technology allow us to analyze the epigenome comprehensively. In this review, we would like to elucidate the mammalian epigenome by profiling T-DMRs, and to address the relationship between the epigenome and the genome. DNA Methylation is a Major Player in the Epigenetic SystemThe major components of the epigenetic system are DNA methylation and histone modifications. In mammals, DNA methylation occurs at the cytosine residues (C) in CpG dinucleotide sequences, and is involved in imprinting, X-inactivation, immobilization of transposable genomic elements, and the regulation of gene activity [3]. ...

Basic mechanics of DNA methylation and the unique landscape of the DNA methylome in metal-induced carcinogenesis

“…TEs are DNA sequences that can change their relative position (self-transpose) within the genome of a single cell and their activation can result in genomic instability. Methylation of TEs silences these sequences and prevents them from mobilizing to other genomic locations (Yagi et al, 2012). When CGs in TEs lose their methylation, the TEs become mobilized and insert into genomic locations such as regulatory sequences and gene bodies and may disrupt gene expression.…”

“…When CGs in TEs lose their methylation, the TEs become mobilized and insert into genomic locations such as regulatory sequences and gene bodies and may disrupt gene expression. Differential methylation of TEs located within or near promoters of genes can also interfere with normal gene expression (Dolinoy et al, 2006, Yagi et al, 2012). …”

DNA methylation profile dynamics of tissue-dependent and differentially methylated regions during mouse brain development

“…Approximately 50% of promoters are associated with CGIs. D-REAM also has [7,25]. Only limited numbers of genes are coincided to be predicted to have DMRs in NSph: Gfap , which have been shown to have DMR hypomethylated in E14.5NSph [18], was not included in our gene list because of lacking HpyCH4IV site in the proximal promoter region: DMRs on Ntng1 , which was identified in this study, is an example of novel T-DMRs not described in the previous studies.…”

“…Systematic biases are inevitable for any genome-wide DNA methylation analysis: both Microarray-based Integrated Analysis of Methylation by Isoschizomers (MIAMI) [16] and Reduced Representation Bisulfite Sequencing (RRBS) [18], methods used in the previous epigenomic study in NPCs, are inevitably focusing on CGIs because of the biased distribution of MspI recognition sites that they uses for enrichment of fragments [24]; Methylated DNA immunoprecipitation (MeDIP) [17], is known to have bias to high density CpG promoter [25]. Approximately 50% of promoters are associated with CGIs.…”

DNA methylation and its role in the trophoblast cell lineage

“…Non-CpG methylation appears to be more enriched in the genome of germ cells and ES cells (Ramsahoye et al, 2000;Shirane et al, 2013). Although CpG methylation is associated mostly with repression of gene expression (Weber et al, 2007;Yagi et al, 2008Yagi et al, , 2012, the presence of methylated promoters with low CpG content at transcriptionally active genes has also been noted by genome-wide DNA methylation and gene expression analyses (Weber et al, 2007). This suggests that sparse CpG methylation does not interfere with the transcription machinery and/or that CpG methylation in a particular sequence context activates transcription.…”