Small RNA guides for de novo DNA methylation in mammalian germ cells

Abstract

Cytosine methylation provides a stable, heritable, and reversible mark for transcriptional repression. Reprogramming of the methylation repertoire at each passage through the germline is a mammalian characteristic. An erasure step allows the acquisition of an epigenetic state unique to the germ cell lineage and central to the transmission of totipotency over generations. Subsequent initiation of gametic methylation has a major impact on fertility, by silencing parasitic transposable elements (TEs) and providing a parental mark for the monoallelic expression of imprinted genes. To control the overwhelming genomic contribution of TEs and their deleterious effects on gamete integrity, a variety of repressive mechanisms, including DNA methylation in mammals, have been developed over the course of evolution to lead to their suppression. Gametic de novo methylation involves the activity of the DNA methyltransferases Dnmt3A and Dnmt3B, assisted by their regulatory factor Dnmt3L. Studies based on structural, biochemical, and DNA analyses provided information as to how these proteins functionally interact to add methyl groups on cytosines within CG dinucleotides. Besides this general recognition of CG sites, additional signals targeting DNA methylation to specific genomic sequences are progressively elucidated. Specific histone modifications and energy-dependent chromatin remodeling enzymes have been shown to regulate the accessibility of DNA methyltransferases to their substrates. A specific class of small RNAs, the piwi-interacting RNAs (piRNAs), was most recently proposed to guide DNA methylation in male germ cells in the mouse. The developmental analysis performed by Kuramochi-Miyagawa et al. (2008) in the context of normal and Piwi-mutant spermatogenesis, published in the previous issue of Genes & Development, definitely supports the existence of an RNA-directed pathway triggering the initiation of DNA methylation in the mammalian germline. The different pieces of the puzzle now lay on the table. Deciphering how these different pieces connect together to control the establishment of gametic methylation patterns at the right time and at the right place will be the next exciting challenge in the field.

Files

Additional details