Evolving insights on how cytosine methylation affects protein-DNA binding

Machado, Ana Carolina Dantas; Zhou, Tianyin; Rao, Satyanarayan; Goel, Pragya; Rastogi, Chaitanya; Lazarovici, Allan; Bussemaker, Harmen J.; Rohs, Remo

doi:10.1093/bfgp/elu040

Cited by 107 publications

(82 citation statements)

References 111 publications

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“…In spite of the very small chemical change, the addition of the methyl group to the C5 position of cytosine can influence the major groove readout, using hydrophobic contacts and shape readout in the minor groove . Do the eight CpG methylations affect the local structures of the DNA and the histone octamer?…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of human nucleosome core particle containing enzymatically introduced CpG methylation

et al. 2016

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Cytosine methylation, predominantly of the CpG sequence in vertebrates, is one of the major epigenetic modifications crucially involved in the control of gene expression. Due to the difficulty of reconstituting site‐specifically methylated nucleosomal DNA at crystallization quality, most structural analyses of CpG methylation have been performed using chemically synthesized oligonucleotides, There has been just one recent study of nucleosome core particles (NCPs) reconstituted with nonpalindromic human satellite 2‐derived DNAs. Through the preparation of a 146‐bp palindromic α‐satellite‐based nucleosomal DNA containing four CpG dinucleotide sequences and its enzymatic methylation and restriction, we reconstituted a ‘symmetric’ human CpG‐methylated nucleosome core particle (NCP). We solved the crystal structures of the CpG‐methylated and unmodified NCPs at 2.6 and 3.0 Å resolution, respectively. We observed the electron densities of two methyl groups, among the eight 5‐methylcytosines introduced in the CpG‐fully methylated NCP. There were no obvious structural differences between the CpG‐methylated ‘symmetric NCP’ and the unmodified NCP. The preparation of a crystallization‐grade CpG‐methylated NCP provides a platform for the analysis of CpG‐methyl reader and eraser proteins.

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Section: Discussionmentioning

confidence: 99%

Crystal structure of human nucleosome core particle containing enzymatically introduced CpG methylation

et al. 2016

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“…Both in vitro DNase I digestion assays and structural studies indicate that methylation has a profound impact on DNA structure and shape (for an in-depth review see REF. 69). Adding a methyl group to the cytosine could affect the local DNA shape, as evidenced by the altered DNase I digestion rate and patterns 70,71 .…”

Section: Features Of Methylated-dna–protein Interactionmentioning

confidence: 99%

Transcription factors as readers and effectors of DNA methylation

Zhu¹,

2016

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Recent technological advances have made it possible to decode DNA methylomes at single-base-pair resolution under various physiological conditions. Many aberrant or differentially methylated sites have been discovered, but the mechanisms by which changes in DNA methylation lead to observed phenotypes, such as cancer, remain elusive. The classical view of methylation-mediated protein-DNA interactions is that only proteins with a methyl-CpG binding domain (MBD) can interact with methylated DNA. However, evidence is emerging to suggest that transcription factors lacking a MBD can also interact with methylated DNA. The identification of these proteins and the elucidation of their characteristics and the biological consequences of methylation-dependent transcription factor-DNA interactions are important stepping stones towards a mechanistic understanding of methylation-mediated biological processes, which have crucial implications for human development and disease.

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“…The covalent addition of methyl groups to cytosine residues of DNA is catalysed by a family of enzymes known as DNA [33,34]. In one of the first studies to examine effects of manipulating a specific epigenetic mechanism on sexual differentiation, Kurian et al [35] used small interfering RNAs to decrease MeCP2 expression in the amygdala of neonatal rats and measured several behaviours at weaning.…”

Section: Dna Methylation and Sexual Differentiation Of The Brain And mentioning

confidence: 99%

Epigenetic mechanisms in sexual differentiation of the brain and behaviour

Forger¹

2016

Phil. Trans. R. Soc. B

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One contribution of 16 to a theme issue 'Multifaceted origins of sex differences in the brain'.Subject Areas: behaviour, developmental biology, genetics, neuroscience Keywords:DNA methylation, histone, medial preoptic area, bed nucleus of the stria terminalis, sex difference Author for correspondence: Nancy G. Forger e-mail: nforger@gsu.edu Epigenetic mechanisms in sexual differentiation of the brain and behaviour Nancy G. Forger Neuroscience Institute, Georgia State University, Atlanta, GA 30307, USA Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

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Evolving insights on how cytosine methylation affects protein-DNA binding

Cited by 107 publications

References 111 publications

Crystal structure of human nucleosome core particle containing enzymatically introduced CpG methylation

Crystal structure of human nucleosome core particle containing enzymatically introduced CpG methylation

Transcription factors as readers and effectors of DNA methylation

Epigenetic mechanisms in sexual differentiation of the brain and behaviour

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