Evolved readers of 5-carboxylcytosine CpG dyads reveal a high versatility of the methyl-CpG-binding domain for recognition of noncanonical epigenetic marks

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dc.contributor.authorKosel, Brinja
dc.contributor.authorBigler, Katrin
dc.contributor.authorBuchmuller, Benjamin C.
dc.contributor.authorAcharyya, Suchandra R.
dc.contributor.authorLinser, Rasmus
dc.contributor.authorSummerer, Daniel
dc.date.accessioned2026-01-15T09:20:11Z
dc.date.available2026-01-15T09:20:11Z
dc.date.issued2024-01-29
dc.description.abstractMammalian genomes are regulated by epigenetic cytosine (C) modifications in palindromic CpG dyads. Including canonical cytosine 5-methylation (mC), a total of four different 5-modifications can theoretically co-exist in the two strands of a CpG, giving rise to a complex array of combinatorial marks with unique regulatory potentials. While tailored readers for individual marks could serve as versatile tools to study their functions, it has been unclear whether a natural protein scaffold would allow selective recognition of marks that vastly differ from canonical, symmetrically methylated CpGs. We conduct directed evolution experiments to generate readers of 5-carboxylcytosine (caC) dyads based on the methyl-CpG-binding domain (MBD), the widely conserved natural reader of mC. Despite the stark steric and chemical differences to mC, we discover highly selective, low nanomolar binders of symmetric and asymmetric caC-dyads. Together with mutational and modelling studies, our findings reveal a striking evolutionary flexibility of the MBD scaffold, allowing it to completely abandon its conserved mC recognition mode in favour of noncanonical dyad recognition, highlighting its potential for epigenetic reader design.en
dc.identifier.urihttp://hdl.handle.net/2003/44682
dc.language.isoen
dc.relation.ispartofseriesAngewandte Chemie / International edition; 63(17)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectEpigenetic cytosine modificationsen
dc.subjectMethyl-CpG-binding domainsen
dc.subjectDNA recognitionen
dc.subjectDirected Evolutionen
dc.subject.ddc540
dc.subject.rswkCytosin
dc.subject.rswkEpigenetik
dc.subject.rswkCpG-Inseln
dc.subject.rswkDNS-Bindung
dc.subject.rswkGerichtete Evolution
dc.titleEvolved readers of 5-carboxylcytosine CpG dyads reveal a high versatility of the methyl-CpG-binding domain for recognition of noncanonical epigenetic marksen
dc.typeText
dc.type.publicationtypeArticle
dcterms.accessRightsopen access
eldorado.dnb.deposittrue
eldorado.doi.registerfalse
eldorado.openaire.projectidentifierinfo:eu-repo/grantAgreement/EC/H2020/723863/EU/Programmable Readers, Writers, and Erasers of the Epigenetic Cytosine Code/EPICODE
eldorado.secondarypublicationtrue
eldorado.secondarypublication.primarycitationB. Kosel, K. Bigler, B. C. Buchmuller, S. R. Acharyya, R. Linser, D. Summerer, Angew. Chem. Int. Ed. 2024, 63, e202318837. https://doi.org/10.1002/anie.202318837
eldorado.secondarypublication.primaryidentifierhttps://doi.org/10.1002/anie.202318837

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