Journal Article

Impact of cytosine methylation on DNA binding specificities of human transcription factors

Yan, Jian, Sahu, Biswajyoti, Zhong, Fan, Khund-Sayeed, Syed, Popov, Alexander, Yin, Yimeng, Das, Pratyush K., Kivioja, Teemu, Taipale, Minna, Domcke, Silvia, Kaasinen, Eevi, Ginno, Paul A., Taipale, Jussi, Dave, Kashyap, Morgunova, Ekaterina, Vinson, Charles, Schübeler, Dirk, Nitta, Kazuhiro R., Jolma, Arttu

2017

Overview

When the DNA bases cytosine and guanine are next to each other, a methyl group is generally added to the pyrimidine, generating a mCpG dinucleotide. This modification alters DNA structure but can also affect function by inhibiting transcription factor (TF) binding. Yin et al. systematically analyzed the effect of CpG methylation on the binding of 542 human TFs (see the Perspective by Hughes and Lambert). In addition to inhibiting binding of some TFs, they found that mCpGs can promote binding of others, particularly TFs involved in development, such as homeodomain proteins. Science , this issue p. eaaj2239 ; see also p. 489 Genome-scale analysis reveals positive and negative binding of transcription factors to methylated CpG dinucleotides. The majority of CpG dinucleotides in the human genome are methylated at cytosine bases. However, active gene regulatory elements are generally hypomethylated relative to their flanking regions, and the binding of some transcription factors (TFs) is diminished by methylation of their target sequences. By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences. Most of these are in the extended homeodomain family. Structural analysis showed that homeodomain specificity for methylcytosine depends on direct hydrophobic interactions with the methylcytosine 5-methyl group. This study provides a systematic examination of the effect of an epigenetic DNA modification on human TF binding specificity and reveals that many developmentally important proteins display preference for mCpG-containing sequences.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Binding / Bisulfite / CDX2 protein / Cell differentiation / Cell division / Chromatin / CpG Islands / Crystal structure / Cytosine / Cytosine - chemistry / Deoxyribonucleic acid / Differentiation (biology) / Dinucleoside Phosphates - chemistry / DNA / DNA - chemistry / DNA Methylation / DNA microarrays / DNA structure / Embryo cells / Embryogenesis / Enrichment / Epigenesis, Genetic / Epigenetics / ETS protein / Evolution / Fractions / Gene regulation / Gene sequencing / Gene silencing / Genes / Genetics / Genome, Human / Genomes / Guanine / Heredity / Homeobox / Humans / Hydrophobicity / Immunoprecipitation / Individualized Instruction / Inhibition / Ligands / Logos / Methylation / Nucleotide sequence / Nucleotides / Preferences / Protein Binding / Protein Domains / Proteins / Regulatory mechanisms (biology) / RESEARCH ARTICLE SUMMARY / SELEX Aptamer Technique / Stem cells / Steric hindrance / Structural analysis / Structural Analysis (Linguistics) / Structural Analysis (Science) / Transcription factors / Transcription Factors - chemistry / Transcription Factors - classification