期刊
BRIEFINGS IN FUNCTIONAL GENOMICS
卷 14, 期 1, 页码 61-73出版社
OXFORD UNIV PRESS
DOI: 10.1093/bfgp/elu040
关键词
epigenetics; DNA methylation; 5-methylcytosine; protein-DNA interactions; DNase I endonuclease; transcription factors
资金
- National Institutes of Health [R01HG003008, R01GM106056, U01GM103804, U54CA121852]
- Alfred P. Sloan Foundation
- National Science Foundation [MCB-1413539]
- Direct For Biological Sciences [1413539] Funding Source: National Science Foundation
- NATIONAL CANCER INSTITUTE [U54CA121852] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG003008] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM106056, U01GM103804, T32GM082797] Funding Source: NIH RePORTER
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.
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