Chromatin-dependent motif syntax defines differentiation trajectories
Date
2025
Authors
Durdu, S.
Iskar, M.
Isbel, L.
Hoerner, L.
Wirbelauer, C.
Burger, L.
Hess, D.
Iesmantavicius, V.
Schübeler, D.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Molecular Cell, 2025; 85(15):2900-2918
Statement of Responsibility
Sevi Durdu, Murat Iskar, Luke Isbel, Leslie Hoerner, Christiane Wirbelauer, Lukas Burger, Daniel Hess, Vytautas Iesmantavicius, and Dirk Schübeler
Conference Name
Abstract
Transcription 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.
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Dissertation Note
Provenance
Description
STAR Methods: e1-e16
Access Status
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/).