ZBTB38 is transcription factor that binds to DNA in an atypical way

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A publication in Epigenetics, led by the ‘Epigenetics, DNA Replication and Cancer’ team with the help of a Université Paris Cité team, Dynamics of DNA Methylation in Eukaryotic Genomes, describes how a transcription factor called ZBTB38 binds to DNA in the cell. ZBTB38 encodes a transcription factor important for growth regulation (de Dieuleveult  and Miotto, 2018). The study shows an atypical way of DNA binding that has never been described before. ZBTB38 uses two DNA binding domains located in the central and terminal parts of the protein, and recognises two motifs on DNA, both of which are methylated on a central CpG position.

A transcription factor is a protein required for the regulation of gene expression. It acts by binding to consensus DNA sequences, often located at the promoters and regulatory regions of the gene, and allows the recruitment and assembly of transcription initiation or repression complexes.

DNA methylation plays a major role in the regulation of gene expression. The addition of a methyl group (me) to Cytosine-Guanine (CpG) dinucleotides is interfering with or promoting the binding of transcription factors to their genomic targets. meCpG is frequently associated with the inhibition of gene expression by blocking the DNA binding of transcription factors. However, there are transcription factors that are insensitive to meCpG sequences and others that have a high affinity for meCpG sequences. In the latter category, there are many zinc finger transcription factors such as ZBTB38.

In 2016, PA Defossez's team (Dynamics of DNA Methylation in Eukaryotic Genomes) identified the transcription factor ZBTB38 as binding methylated DNA through several in vitro analyses (Filion et al., 2016). DNA binding is mediated by a central zinc finger domain, also present in the ZBTB4 and ZBTB33 proteins (Filion et al., 2016). A group in the US, led by Bethany A. Buck-Koehntop, has also identified a second domain in the C-terminal part of the protein capable of binding a methylated DNA motif (Hudson et al., 2018). The ZBTB38 protein is thus believed to harbor two DNA-binding domains, each capable of recognising a methylated CpG sequence.

Claire Marchal, a PhD student in our team, tested this hypothesis in the cell. The study shows that ZBTB38 is indeed able to bind 2 methylated DNA motifs in the cell and these motifs are similar to the motifs previously identified by in vitro assays. ZBTB38 is therefore the first transcription factor whose binding specificity is mediated by 2 domains and 2 methylated motifs. The study also reveals that the target genes of ZBTB38 are so-called housekeeping genes, involved in the regulation of cellular metabolism, and associated with numerous pathologies such as cancer.

Ultimately, the study demonstrates an atypical DNA binding mode for the transcription factor ZBTB38 in the cell.

Further information

Marchal C, Defossez PA, Miotto B. Context-dependent CpG methylation directs cell-specific binding of transcription factor ZBTB38. Epigenetics. 2022 Aug 24:1-22. doi: 10.1080/15592294.2022.2111135. Epub ahead of print. PMID: 36000449.

Articles cited:

de Dieuleveult M, Miotto B. DNA Methylation and Chromatin: Role(s) of Methyl-CpG-Binding Protein ZBTB38. Epigenet Insights. 2018 Nov 19;11:2516865718811117. doi: 10.1177/2516865718811117. PMID: 30480223; PMCID: PMC6243405.

Filion GJ, Zhenilo S, Salozhin S, Yamada D, Prokhortchouk E, Defossez PA. A family of human zinc finger proteins that bind methylated DNA and repress transcription. Mol Cell Biol. 2006 Jan;26(1):169-81. doi: 10.1128/MCB.26.1.169-181.2006. PMID: 16354688; PMCID: PMC1317629.

Hudson NO, Whitby FG, Buck-Koehntop BA. Structural insights into methylated DNA recognition by the C-terminal zinc fingers of the DNA reader protein ZBTB38. J Biol Chem. 2018 Dec 21;293(51):19835-19843. doi: 10.1074/jbc.RA118.005147. Epub 2018 Oct 24. PMID: 30355731; PMCID: PMC6314133

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Benoit Miotto

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