Chromatin-dependent motif syntax defines differentiation trajectories

Simple item page
dc.contributor.authorDurdu, S.
dc.contributor.authorIskar, M.
dc.contributor.authorIsbel, L.
dc.contributor.authorHoerner, L.
dc.contributor.authorWirbelauer, C.
dc.contributor.authorBurger, L.
dc.contributor.authorHess, D.
dc.contributor.authorIesmantavicius, V.
dc.contributor.authorSchübeler, D.
dc.date.issued2025
dc.descriptionSTAR Methods: e1-e16
dc.description.abstractTranscription factors (TFs) recognizing DNA motifs within regulatory regions drive cell identity. Despite recent advances, their specificity remains incompletely understood. Here, we address this by contrasting two TFs, Neurogenin-2 (NGN2) and MyoD1, which recognize ubiquitous E-box motifs yet drive distinct cell fates toward neurons and muscles, respectively. Upon induction in mouse embryonic stem cells, we monitor binding across differentiation, employing an interpretable machine learning approach that integrates preexisting DNA accessibility. This reveals a chromatin-dependent motif syntax, delineating both common and factorspecific binding, validated by cellular and in vitro assays. Shared binding sites reside in open chromatin, locally influenced by nucleosomes. In contrast, factor-specific binding in closed chromatin involves NGN2 and MyoD1 acting as pioneer factors, influenced by motif variant frequencies, motif spacing, and interaction partners, which together account for subsequent lineage divergence. Transferring our methodology to other models demonstrates how a combination of opportunistic binding and context-specific chromatin-opening underpin TF specificity, driving differentiation trajectories.
dc.description.statementofresponsibilitySevi Durdu, Murat Iskar, Luke Isbel, Leslie Hoerner, Christiane Wirbelauer, Lukas Burger, Daniel Hess, Vytautas Iesmantavicius, and Dirk Schübeler
dc.identifier.citationMolecular Cell, 2025; 85(15):2900-2918
dc.identifier.doi10.1016/j.molcel.2025.07.005
dc.identifier.issn1097-2765
dc.identifier.issn1097-4164
dc.identifier.orcidIsbel, L. [0000-0002-5270-4347]
dc.identifier.urihttps://hdl.handle.net/2440/147935
dc.language.isoen
dc.publisherCell Press
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1148380
dc.rights© 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
dc.source.urihttps://doi.org/10.1016/j.molcel.2025.07.005
dc.subjecttranscription factor specificity; motif syntax; motif variants; pioneer factors; chromatin accessibility; gene regulation; cell differentiation; machine learning; predictive models; E-box
dc.subject.meshAnimals
dc.subject.meshBasic Helix-Loop-Helix Transcription Factors
dc.subject.meshBinding Sites
dc.subject.meshCell Differentiation
dc.subject.meshCell Lineage
dc.subject.meshChromatin
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshMouse Embryonic Stem Cells
dc.subject.meshMyoD Protein
dc.subject.meshNerve Tissue Proteins
dc.subject.meshNeurons
dc.subject.meshNucleosomes
dc.subject.meshNucleotide Motifs
dc.subject.meshProtein Binding
dc.titleChromatin-dependent motif syntax defines differentiation trajectories
dc.typeJournal article
pubs.publication-statusPublished

Files

Collections

Research Outputs