In multicellular organisms, cells and tissues form as a result of differentiation of a single fertilized egg, and phenotypes are inherited over several cell generations without alteration in the DNA sequences. Epigenetic systems are recognized as memory systems for these inheritable gene functions, and in mammals, they comprise DNA methylation and histone modifications of chromatin (fig A). DNA methylation in tissue-dependent and differentially methylated regions (T-DMRs) is involved in expression of tissue-specific genes as well as expression of key transcription factors that constitute transcription networks governing tissue or cell specificity. Abnormal methylation of T-DMRs has been implicated in the pathogenesis of certain diseases. DNA methylation occurs at the cytosine residue of CpG dinucleotides, which are unevenly distributed within the mammalian genome. CpG islands (CGIs) have been identified as CpG-rich regions that are associated with approximately 50% of the promoter regions in the mouse genome. Previous genome-wide DNA methylation analyses, focusing on CGIs, have indicated that every cell and tissue type has a unique DNA methylation profile, comprising at least hundreds of T-DMRs, and these data suggested that a methylation profile could be used to identify cell types (Shiota 2004). To illustrate the genome-wide mouse DNA methylation profile, we developed a method involving T-DMR profiling with restriction tag-mediated amplification (D-REAM) (Fig. B), which combined microarray technology and modified ligation-mediated polymerase chain reaction (LM-PCR). Using D-REAM, we can obtain moderate resolution of mammalian epigenome, which consists of T-DMRs. Using a mouse promoter tiling array covering a region from -6 to 2.5 kb (approximately 30,000 transcription start sites), we found that over 3,000 T-DMRs are hypomethylated in liver compared to cerebrum. The DNA methylation profile of liver was distinct from that of kidney and spleen. The data indicate that multi-layered regulation of tissue-specific gene function could be elucidated by DNA methylation tissue profiling (Yagi et al. 2008).



Shiota K. DNA methylation profiles of CpG islands for cellular differentiation and development in mammals. Cytogenet Genome Res, 105 (2004) 325-334.

Yagi S, Hirabayashi K, Sato S, Li W, Takahashi Y, Hirakawa T, Wu G, Hattori N, Hattori N, Ohgane J, Tanaka S, Liu XS and Shiota K. DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression. Genome Research 18 (12) 1969-1978.

Johnson WE*, Li W*, Meyer CA*, Gottardo R, Carroll JS, Brown M and Liu XS. Model-based analysis of tiling-arrays for ChIP-chip. Proc. Natl. Acad. Sci. USA 103 (2006) 12457-12462. (*Joint first authors) MAT Website

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