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Review
. 2018 Oct 7;23(10):2555.
doi: 10.3390/molecules23102555.

Zinc Finger Readers of Methylated DNA

Nicholas O Hudson  1 , Bethany A Buck-Koehntop  2
Affiliations
Review

Zinc Finger Readers of Methylated DNA

Nicholas O Hudson et al. Molecules. .

Abstract

DNA methylation is a prevalent epigenetic modification involved in regulating a number of essential cellular processes, including genomic accessibility and transcriptional outcomes. As such, aberrant alterations in global DNA methylation patterns have been associated with a growing number of disease conditions. Nevertheless, the full mechanisms by which DNA methylation information is interpreted and translated into genomic responses is not yet fully understood. Methyl-CpG binding proteins (MBPs) function as important mediators of this essential process by selectively reading DNA methylation signals and translating this information into down-stream cellular outcomes. The Cys₂His₂ zinc finger scaffold is one of the most abundant DNA binding motifs found within human transcription factors, yet only a few zinc finger containing proteins capable of conferring selectivity for mCpG over CpG sites have been characterized. This review summarizes our current structural understanding for the mechanisms by which the zinc finger MBPs evaluated to date read this essential epigenetic mark. Further, some of the biological implications for mCpG readout elicited by this family of MBPs are discussed.

Keywords: DNA methylation; epigenetics; methyl-CpG binding proteins; protein-DNA interactions; zinc finger.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Domain organization for the characterized zinc finger (ZF) methyl-CpG binding proteins (MBPs). For each protein, the ZFs shown to have methyl sensitivity are underlined and the target DNA sequence utilized for high-resolution structural investigations are depicted alongside the Protein Data Bank (PDB) identification for the structures shown in Figure 2. M refers to methylated cytosine. POZ: Pox virus and zing finger domain; KRAB: Krüppel-associated box.
Figure 2
Figure 2
High-resolution crystal structures for members of the ZF MBP family in complex with their respective methylated DNA targets. (a) Human ZBTB33 in complex with a methylated DNA sequence derived from the E-cadherin promoter (PDB 4F6N); (b) mouse Zfp57 in complex with a methylated DNA sequence present in imprinting control regions (PDB 4GZN); (c) mouse Klf4 (Krüppel-like factor 4) in complex with its cognate methylated DNA sequence (PDB 4M9E); (d) human Egr1 (growth response protein 1) in complex with its cognate methylated DNA sequence (PDB 4X91); (e) human CTCF (CCCTC-binding factor) in complex with a methylated version of its core recognition sequence (PDB 5T00). Red spheres indicate water molecules. Red dotted lines denote classical hydrogen bond interactions; blue dotted lines indicate CH···O type hydrogen bonds, and black dotted lines designate van der Waals interactions. For each zoomed-in image, the amino acid side chain color designation matches that of the ZF from which it is derived in the full structural image depicted above.
Figure 3
Figure 3
DNA shape analyses for the DNA targets of ZBTB33, Zfp57, and Klf4 used for crystallography in their free unmodified CpG (black), free methyl-CpG (red), and methyl-CpG protein complexed (blue) forms. The blue rectangles are centered on the core CpG dinucleotides.
Figure 4
Figure 4
Sequence alignment for additional ZF proteins that share the conserved lysine/glutamate residue pair (boxed) that was shown for the C-terminal ZFs of ZBTB38 to participate in selective mCpG recognition.
See this image and copyright information in PMC

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