Design principles of cell-state-specific enhancers in hematopoiesis

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  • dc.contributor.author Frömel, Robert
  • dc.contributor.author Rühle, Julia
  • dc.contributor.author Bernal, Aina
  • dc.contributor.author Szu-Tu, Chelsea
  • dc.contributor.author Pacheco Pastor, Felix
  • dc.contributor.author Martínez Corral, Rosa, 1991-
  • dc.contributor.author Velten, Lars
  • dc.date.accessioned 2025-09-08T11:47:45Z
  • dc.date.available 2025-09-08T11:47:45Z
  • dc.date.issued 2025
  • dc.description.abstract During cellular differentiation, enhancers transform overlapping gradients of transcription factors (TFs) to highly specific gene expression patterns. However, the vast complexity of regulatory DNA impedes the identification of the underlying cis-regulatory rules. Here, we characterized 64,400 fully synthetic DNA sequences to bottom-up dissect design principles of cell-state-specific enhancers in the context of the differentiation of blood stem cells to seven myeloid lineages. Focusing on binding sites for 38 TFs and their pairwise interactions, we found that identical sites displayed both repressive and activating function as a consequence of cell state, site combinatorics, or simply predicted occupancy of a TF on an enhancer. Surprisingly, combinations of activating sites frequently neutralized one another or gained repressive function. These negative synergies convert quantitative imbalances in TF expression into binary activity patterns. We exploit this principle to automatically create enhancers with specificity to user-defined combinations of hematopoietic progenitor cell states from scratch.
  • dc.description.sponsorship This study was financed by grants from the Spanish Ministry of Science, Innovation and Universities MCIU/AEI/10.13039/501100011033 (grant PID2019-108082GA-I00 to L.V.; and grant RYC2021-033860-I cofounded by European Union NextGenerationEU/PRTR to R.M.-C.), the Ministry of Science and Innovation (PID2022-142210NA-I00 funded by MCIN/AEI/10.13039/501100011033 / FEDER, UE to R.M.-C.; and pre-doctoral fellowship PRE2021-097675 funded by MCIN/AEI/10.13039/501100011033 and FSE+ to J.R.). This project has received funding from the European Union's Horizon Europe under the grant agreement no. 101041399 (ERC-StG AI4SYN to L.V.). F.P.P. was supported by the predoctoral program AGAUR-FI grants (2023 FI_I 00776), Joan Oró of the Secretariat of Universities and Research of the Department of Research and Universities of the Generalitat de Catalunya, and the European Social Fund Plus. The authors acknowledge support by the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S and MCIN/AEI /10.13039/501100011033) and the Generalitat de Catalunya through the CERCA programme and to the EMBL partnership. We are grateful to the CRG Core Technologies Programme for their support and assistance in this work. Research for this publication has been partially carried out in the Barcelona Collaboratorium for Modelling and Predictive Biology.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Frömel R, Rühle J, Bernal Martinez A, Szu-Tu C, Pacheco Pastor F, Martinez-Corral R, et al. Design principles of cell-state-specific enhancers in hematopoiesis. Cell. 2025 Jun 12;188(12):3202-18.e21. DOI: 10.1016/j.cell.2025.04.017
  • dc.identifier.doi http://dx.doi.org/10.1016/j.cell.2025.04.017
  • dc.identifier.issn 0092-8674
  • dc.identifier.uri http://hdl.handle.net/10230/71147
  • dc.language.iso eng
  • dc.publisher Elsevier
  • dc.relation.ispartof Cell. 2025 Jun 12;188(12):3202-18.e21
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/101041399
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-108082GA-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-142210NA-I00
  • dc.rights © 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
  • dc.subject.keyword MPRA
  • dc.subject.keyword Cellular differentiation
  • dc.subject.keyword Functional genomics
  • dc.subject.keyword Gene regulation
  • dc.subject.keyword Hematopoiesis
  • dc.subject.keyword Synthetic enhancers
  • dc.subject.keyword Transcription factors
  • dc.title Design principles of cell-state-specific enhancers in hematopoiesis
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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