DNA Methylation in Development

Abstract

Abstract DNA ( deoxyribonucleic acid ) methylation is an epigenetic modification which can silence gene expression and stabilize repeats. A methyl group is added to cytosine when followed by guanine (CpG) and CpGs are enriched at the promoters of many genes and in retrotransposons. Nevertheless, only a small number of these CpG‐rich genes are actually regulated by methylation. These fall into three classes: imprinted genes, genes on the inactive X and germ cell‐specific genes. Methylation is reprogrammed (erased and re‐established) at two points during development: around implantation and the during germ cell development. DNA methyltransferase 3a ( DNMT3A ) and DNMT3B establish methylation patterns, with the help of the cofactor DNMT3L in the germ cells, then DNMT1 maintains them during mitotic division. Failure of either process leads to developmental defects, sterility or embryonic death. Histone methylation and small RNAs ( ribonucleic acids ) have been implicated in directing the methyltransferases to particular genes or repeats. Key concepts: DNA methylation is associated with transcriptionally inactive chromatin and helps stabilize it. Methylation in mammals occurs exclusively at cytosine followed by guanine (CpG). CpG‐rich regions (CpG islands) are found at the start of many genes and in retrotransposons. Methylation of CpG islands maintains repression on imprinted genes, genes on the inactive X chromosome, germ cell‐specific genes and certain retrotransposons. Three key enzymes are involved, DNMT1, DNMT3A and DNMT3B, together with the cofactor DNMT3L. DNMT1 maintains DNA methylation on all sequences during development. DNMT3A and DNMT3L are essential for imprinting and retrotransposon repression in the germ cells. There is a developmental cycle of changes in the level of genomic methylation, which is necessary for the correct reprogramming of imprinted and X‐chromosome genes for the next generation. Evidence is growing that histone modifications determine which DNA sequences become methylated.