title: Evolving insights on how cytosine methylation affects protein-DNA binding.
abstract: Many anecdotal observations exist of a regulatory effect of DNA methylation on gene expression. However, in general, the underlying mechanisms of this effect are poorly understood. In this review, we summarize what is currently known about how this important, but mysterious, epigenetic mark impacts cellular functions. Cytosine methylation can abrogate or enhance interactions with DNA-binding proteins, or it may have no effect, depending on the context. Despite being only a small chemical change, the addition of a methyl group to cytosine can affect base readout via hydrophobic contacts in the major groove and shape readout via electrostatic contacts in the minor groove. We discuss the recent discovery that CpG methylation increases DNase I cleavage at adjacent positions by an order of magnitude through altering the local 3D DNA shape and the possible implications of this structural insight for understanding the methylation sensitivity of transcription factors (TFs). Additionally, 5-methylcytosines change the stability of nucleosomes and, thus, affect the local chromatin structure and access of TFs to genomic DNA. Given these complexities, it seems unlikely that the influence of DNA methylation on protein-DNA binding can be captured in a small set of general rules. Hence, data-driven approaches may be essential to gain a better understanding of these mechanisms.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Dantas Machado
authors.forename: Tianyin
authors.initials: T
authors.lastname: Zhou
authors.forename: Satyanarayan
authors.initials: S
authors.lastname: Rao
authors.forename: Pragya
authors.initials: P
authors.lastname: Goel
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Rastogi
authors.forename: Allan
authors.initials: A
authors.lastname: Lazarovici
authors.forename: Harmen J
authors.initials: HJ
authors.lastname: Bussemaker
authors.forename: Remo
authors.initials: R
authors.lastname: Rohs
mesh_terms: D000818:Animals; D001483:Base Sequence; D003596:Cytosine / Q000378:metabolism*; D019175:DNA Methylation; D006801:Humans; D008958:Models, Molecular; D009707:Nucleosomes / Q000378:metabolism; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D009707:Nucleosomes; D014157:Transcription Factors; D003596:Cytosine
keywords: 5-methylcytosine; DNA methylation; DNase I endonuclease; epigenetics; protein–DNA interactions; transcription factors