Toward a Mechanistic Understanding of DNA Methylation Readout by Transcription Factors

Judith F Kribelbauer; Xiang-Jun Lu; Remo Rohs; Richard S Mann; Harmen J Bussemaker

doi:10.1016/j.jmb.2019.10.021

Toward a Mechanistic Understanding of DNA Methylation Readout by Transcription Factors

J Mol Biol. 2020 Mar 13;432(6):1801-1815. doi: 10.1016/j.jmb.2019.10.021. Epub 2019 Nov 2.

Authors

Judith F Kribelbauer¹, Xiang-Jun Lu², Remo Rohs³, Richard S Mann⁴, Harmen J Bussemaker⁵

Affiliations

¹ Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA.
² Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
³ Quantitative and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA; Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA; Department of Physics & Astronomy, University of Southern California, Los Angeles, CA 90089, USA; Department of Computer Science, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Neuroscience, Columbia University, New York, NY 10027, USA.
⁵ Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA. Electronic address: hjb2004@columbia.edu.

Abstract

Epigenetic DNA modification impacts gene expression, but the underlying molecular mechanisms are only partly understood. Adding a methyl group to a cytosine base locally modifies the structural features of DNA in multiple ways, which may change the interaction with DNA-binding transcription factors (TFs) and trigger a cascade of downstream molecular events. Cells can be probed using various functional genomics assays, but it is difficult to disentangle the confounded effects of DNA modification on TF binding, chromatin accessibility, intranuclear variation in local TF concentration, and rate of transcription. Here we discuss how high-throughput in vitro profiling of protein-DNA interactions has enabled comprehensive characterization and quantification of the methylation sensitivity of TFs. Despite the limited structural data for DNA containing methylated cytosine, automated analysis of structural information in the Protein Data Bank (PDB) shows how 5-methylcytosine (5mC) can be recognized in various ways by amino acid side chains. We discuss how a context-dependent effect of methylation on DNA groove geometry can affect DNA binding by homeodomain proteins and how principled modeling of ChIP-seq data can overcome the confounding that makes the interpretation of in vivo data challenging. The emerging picture is that epigenetic modifications affect TF binding in a highly context-specific manner, with a direction and effect size that depend critically on their position within the TF binding site and the amino acid sequence of the TF. With this improved mechanistic knowledge, we have come closer to understanding how cells use DNA modification to acquire, retain, and change their identity.

Keywords: Confounding effects in the analysis of in vivo binding data (ChIP-seq); Epigenetic modification of DNA; High-throughput in vitro assays; Quantifying the effect of cytosine methylation on transcription factor binding; Structural mechanisms including the effect of methylation on DNA shape.

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Review

Abstract

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