Regulation of the stem cell epigenome by REST
Bithell A., Buckley NJ.
© Cambridge University Press 2012. Introduction Complex gene regulatory networks control the acquisition and maintenance of cellular phenotype and function. This is nowhere more evident than in stem cell maintenance and differentiation. Stem cells are unique in that they can self-renew yet retain the potential to differentiate into specialized cell types in response to signals received during development, injury, or disease. As such they act as a repository of cells that have the potential to be recruited to repair injury or degeneration. This unique plasticity is maintained by signals released from the stem cell niche that coordinately regulate the stem cell transcriptome and epigenome. To a large extent, the hunt for molecular hallmarks of “stemness” has focused on identifying either transcriptional regulatory pathways or epigenomic signatures (Cai et al., 2004; Spivakov and Fisher, 2007). However, it is clear that transcriptional and epigenetic regulation are obverse sides of the same coin, since epigenetic modifiers are recruited by transcription factors and, obversely, transcription factor recruitment is determined by the epigenetic status of the target gene chromatin. Consequently, we need to identify factors that act to coordinate regulation of the transcriptome and epigenome. Epigenetic marks largely consist of posttranslational modifications on chromatin (largely, but not exclusively, to N-terminal histone tails or methylation of CpG dinucleotides) which act as a layer of information that does not affect DNA sequence but influences the way in which the genome is “read.” An ever-increasing list of histone modifications (including acetylation, methylation, phosphorylation, and ubiquitination), and the proteins that “read,” “write” (deposit), and remove them, are now known (Kouzarides, 2007; Schones and Zhao, 2008). Much of the recent surge of interest in epigenomics has been fueled by the success of next-generation sequencing platforms in generating whole-genome maps of epigenetic marks (Barski et al., 2007; Meissner et al., 2008). An important concept to emerge is the overturning of the simplistic view of active versus repressive chromatin marks, since it is clear that many marks associated with active chromatin coexist with those associated with repressive chromatin, and this is reflected by the co-recruitment of the corresponding histone-modifying activities (Berger, 2007; Meaney and Ferguson-Smith, 2010).