Epigenetic Signature of Embryonal Stem Cells: A DNA Methylation Perspective

Specific epigenetic features underpin the pluripotency of ES cells. ES cells have a unique DNA methylation signature, express high levels of DNA de novo methyltransferases, and, unlike somatic cells, are capable of methylating exogenously introduced DNA. At the same time, ES cells protect specific CpG dinucleotides from undergoing de novo methylation, a process that clearly mimics what occurs in the normal embryo. ES cells protect CpG island– as well as non-CpG island–promoters that direct expression of genes involved in stem cell identity from de novo methylation. These promoters are apparently protected by virtue of inherent common sequence elements through binding of transcription machinery related factors. These mechanisms are critical for setting up the correct genome methylation pattern, which is mostly stable in somatic cells. Genes that belong to a self-organizing network of transcription that prevents differentiation and promote proliferation and pluripotency, such as Oct-3/4 and Nanog, are silenced during differentiation by histone modification as well as by DNA methylation. Indeed, genetic experiments have supported the notion that histone modification directs DNA methylation, which represents a second-line epigenetic change, the role of which is to permanently silence gene expression, thereby preventing reprogramming.