Interplay between different epigenetic modifications and mechanisms.

Cellular functions including transcription regulation, DNA repair, and DNA replication need to be tightly regulated. DNA sequence can contribute to the regulation of these mechanisms. This is exemplified by the consensus sequences that allow the binding of specific transcription factors, thus regulating transcription rates. Another layer of regulation resides in modifications that do not affect the DNA sequence itself but still results in the modification of chromatin structure and properties, thus affecting the readout of the underlying DNA sequence. These modifications are dubbed as "epigenetic modifications" and include, among others, histone modifications, DNA methylation, and small RNAs. While these events can independently regulate cellular mechanisms, recent studies indicate that joint activities of different epigenetic modifications could result in a common outcome. In this chapter, I will attempt to recapitulate the best known examples of collaborative activities between epigenetic modifications. I will emphasize mostly on the effect of crosstalks between epigenetic modifications on transcription regulation, simply because it is the most exposed and studied aspect of epigenetic interactions. I will also summarize the effect of epigenetic interactions on DNA damage response and DNA repair. The involvement of epigenetic crosstalks in cancer formation, progression, and treatment will be emphasized throughout the manuscript. Due to space restrictions, additional aspects involving histone replacements [Park, Y. J., and Luger, K. (2008). Histone chaperones in nucleosome eviction and histone exchange. Curr. Opin. Struct. Biol.18, 282-289.], histone variants [Boulard, M., Bouvet, P., Kundu, T. K., and Dimitrov, S. (2007). Histone variant nucleosomes: Structure, function and implication in disease. Subcell. Biochem. 41, 71-89; Talbert, P. B., and Henikoff, S. (2010). Histone variants-Ancient wrap artists of the epigenome. Nat. Rev. Mol. Cell Biol.11, 264-275.], and histone modification readers [de la Cruz, X., Lois, S., Sanchez-Molina, S., and Martinez-Balbas, M. A. (2005). Do protein motifs read the histone code? Bioessays27, 164-175; Grewal, S. I., and Jia, S. (2007). Heterochromatin revisited. Nat. Rev. Genet.8, 35-46.] will not be addressed in depth in this chapter, and the reader is referred to the reviews cited here.