Chromatin modification and epigenetic reprogramming in mammalian development

The principal epigenetic mechanisms by which tissue-specific gene-expression patterns and global gene silencing are established and maintained are chromatin modification — including processes such as DNA methylation, histone modification (acetylation, phosphorylation, methylation and ubiquitylation) — and chromatin remodelling. New data show how DNA methylation and histone modification integrate with each other in the epigenetic regulation of genomic imprinting, X inactivation and genome reprogramming. DNA methylation is the heritable epigenetic mark for genomic imprinting, which is established in the developing oocyte and is essential for maintaining the mono-allelic expression of imprinted genes. DNA methyltransferase Dnmt3a and an associated protein Dnmt3l, and the histone methyltransferases Suv39h1 and Suv39h2, are required for spermatogenesis. DNA methylation undergoes dynamic changes during early embryonic development, and genome-wide demethylation (after fertilization) and remethylation (after the implantation of a blastocyst) have an essential role in genome reprogramming. X inactivation is regulated by several factors, including non-coding RNAs (Xist and Tsix), DNA methylation, histone acetylation and deacetylation, histone methylation and Polycomb-group proteins. Reprogramming of somatic cell nuclei in enucleated oocytes by nuclear transfer resets the epigenetic programme for embryonic development. Studies of the epigenetic regulation of chromatin and gene expression in development will help to elucidate the underlying causes of certain human diseases. A greater understanding of these processes will also aid research into the clinical application of pluripotent stem cells or progenitor cells in cell-replacement therapy and into new drugs that target epigenetic regulators for use in treating cancer and certain developmental disorders.