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Grant support

We thank M. T. Kanemaki for the degron plasmids; R. Guigo's laboratory, and S. Perez-Lluch in particular, for the H3K27ac and H3K4me1 ChIP-seq, produced in the framework of the RNA-MAPS project (ERC-2011-AdG-294653-RNA-MAPS); Y. Cuartero for help with sequencing and CTCF ChIP-seq; C. Segura for help with immunofluorescence microscopy; the CRG Genomics and flow cytometry core facilities and the CRG-CNAG Sequencing Unit for sequencing; and members of T.G.'s laboratory for discussions. This work was supported by the European Research Council under the 7th Framework Programme FP7/2007-2013 (ERC Synergy Grant 4D-Genome, grant agreement 609989, to T.G. and M.A.M.-R.), the Ministerio de Educacion y Ciencia (SAF.2012-37167, to T.G., and BFU2017-85926-P, to M.A.M.-R.), the AGAUR (to T.G.) and the Marato TV3 (201611) (to M.A.M.-R.). P.C. was supported by the Deutsche Forschungsgemeinschaft (SFB860, SPP1935, EXC 2067/1-390729940), the European Research Council (advanced investigator grant TRANSREGULON, grant agreement no. 693023) and the Volkswagen Foundation. G.S. was supported by a Marie Sklodowska-Curie fellowship (H2020-MSCA-IF-2016, miRStem) and by the 'Fundacion Cientifica de la Asociacion Espanola Contra el Cancer'. T.V.T. was supported by Juan de la Cierva postdoctoral fellowship (MINECO; FJCI-2014-22946). B.B. was supported by the fellowship 2017FI_B00722 from the Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement (Generalitat de Catalunya) and the European Social Fund (ESF). R.S. was supported by a Netherlands Organisation for Scientific Research Veni fellowship (91617114) and an Erasmus MC Fellowship. We also acknowledge support from 'Centro de Excelencia Severo Ochoa 2013-2017' (SEV-20120208), the Spanish Ministry of Science and Innovation to the EMBL partnership and the CERCA Program Generalitat de Catalunya to the CRG, as well as the support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the Generalitat de Catalunya through Departament de Salut and Departament d'Empresa i Coneixement, and co-financing by the Spanish Ministry of Science and Innovation with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program to CNAG.

Analysis of institutional authors

Stik, GCorresponding AuthorVidal, EAuthorBarrero, MAuthorCuartero, SAuthorVila-Casadesús, MAuthorMendieta-Esteban, JAuthorBerenguer, CAuthorAbad, AAuthorBorsari, BAuthorLe Dily, FAuthorMarti-Renom, MaAuthorGraf, TCorresponding Author

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July 6, 2020
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CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response

Publicated to:Nature Genetics. 52 (7): 655-+ - 2020-07-01 52(7), DOI: 10.1038/s41588-020-0643-0

Authors: Stik, G; Vidal, E; Barrero, M; Cuartero, S; Vila-Casadesus, M; Mendieta-Esteban, J; Tian, TV; Choi, J; Berenguer, C; Abad, A; Borsari, B; le Dily, F; Cramer, P; Marti-Renom, MA; Stadhouders, R; Graf, T

Affiliations

Barcelona Inst Sci & Technol BIST, Ctr Genom Regulat CRG, CNAG CRG, Barcelona, Spain - Author
Ctr Genom Regulat CRG, Barcelona, Spain - Author
Erasmus MC, Dept Cell Biol, Rotterdam, Netherlands - Author
Erasmus MC, Dept Pulm Med, Rotterdam, Netherlands - Author
ICREA, Barcelona, Spain - Author
Inst Sci & Technol BIST, Barcelona, Spain - Author
Josep Carreras Leukaemia Res Inst IJC, Barcelona, Spain - Author
Max Planck Inst Biophys Chem, Gottingen, Germany - Author
Univ Pompeu Fabra UPF, Barcelona, Spain - Author
Univ Pompeu Fabra UPF, Barcelona, SpainCtr Genom Regulat CRG, Barcelona, Spain - Author
Vall dHebron Inst Oncol VHIO, Barcelona, Spain - Author
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Abstract

Three-dimensional organization of the genome is important for transcriptional regulation(1-7). In mammals, CTCF and the cohesin complex create submegabase structures with elevated internal chromatin contact frequencies, called topologically associating domains (TADs)(8-12). Although TADs can contribute to transcriptional regulation, ablation of TAD organization by disrupting CTCF or the cohesin complex causes modest gene expression changes(13-16). In contrast, CTCF is required for cell cycle regulation(17), embryonic development and formation of various adult cell types(18). To uncouple the role of CTCF in cell-state transitions and cell proliferation, we studied the effect of CTCF depletion during the conversion of human leukemic B cells into macrophages with minimal cell division. CTCF depletion disrupts TAD organization but not cell transdifferentiation. In contrast, CTCF depletion in induced macrophages impairs the full-blown upregulation of inflammatory genes after exposure to endotoxin. Our results demonstrate that CTCF-dependent genome topology is not strictly required for a functional cell-fate conversion but facilitates a rapid and efficient response to an external stimulus. CTCF is dispensable for transdifferentiation of B cells into induced macrophages despite widespread loss of topologically associating domains. CTCF depletion impairs upregulation of inflammatory genes after endotoxin exposure by destabilizing promoter-enhancer interactions.

Keywords

3d genomebindingchromatin domainscohesindevelopmental enhancersgene-expressionmacrophageprinciplestopological domainsAntigens, differentiationArticleAuxinB lymphocyteB-lymphocytesBone marrow cellCcctc-binding factorCell divisionCell fateCell line, tumorCell proliferationCell transdifferentiationChromatinChromatin immunoprecipitation sequencingCohesinControlled studyCtcf protein, humanDown regulationEndotoxinEnhancer regionFlow cytometryGene expressionGene expression regulationGene targetingHumanHuman cellHumansImmunocompetent cellInflammationInterleukin 6MacrophageMacrophagesMolecular conformationMyelopoiesisPriority journalPromoter regionProtein conformationReal time polymerase chain reactionRna sequencingTranscription factor ctcfTranscription factorsTranscriptomeTranscriptomicsUpregulationWestern blotting

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Nature Genetics due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 2/176, thus managing to position itself as a Q1 (Primer Cuartil), in the category Genetics & Heredity. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 4.81. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 4.23 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 15.12 (source consulted: Dimensions Aug 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-08-02, the following number of citations:

  • WoS: 90
  • Scopus: 91
  • Europe PMC: 62

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-08-02:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 179.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 181 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 113.95.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 114 (Altmetric).
  • The number of mentions in news outlets: 4 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Germany; Netherlands.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Stik, Grégoire) and Last Author (GRAF, THOMAS HEINER).

the authors responsible for correspondence tasks have been Stik, Grégoire and GRAF, THOMAS HEINER.