Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation

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• dc.contributor.author Cieslak, Agata
• dc.contributor.author Gut, Marta
• dc.contributor.author Gut, Ivo Glynne
• dc.contributor.author Asnafi, Vahid
• dc.date.accessioned 2020-11-24T07:08:24Z
• dc.date.issued 2020
• dc.description.abstract Cell differentiation is accompanied by epigenetic changes leading to precise lineage definition and cell identity. Here we present a comprehensive resource of epigenomic data of human T cell precursors along with an integrative analysis of other hematopoietic populations. Although T cell commitment is accompanied by large scale epigenetic changes, we observed that the majority of distal regulatory elements are constitutively unmethylated throughout T cell differentiation, irrespective of their activation status. Among these, the TCRA gene enhancer (Eα) is in an open and unmethylated chromatin structure well before activation. Integrative analyses revealed that the HOXA5-9 transcription factors repress the Eα enhancer at early stages of T cell differentiation, while their decommission is required for TCRA locus activation and enforced αβ T lineage differentiation. Remarkably, the HOXA-mediated repression of Eα is paralleled by the ectopic expression of homeodomain-related oncogenes in T cell acute lymphoblastic leukemia. These results highlight an analogous enhancer repression mechanism at play in normal and cancer conditions, but imposing distinct developmental constraints.
• dc.description.sponsorship Work in the laboratory of S. Spicuglia was supported by recurrent funding from Institut National de la Santé et de la Recherche Médicale and Aix-Marseille University and by specific grants from the European Union’s FP7 Program (agreement 282510-BLUEPRINT), the Foundation for Cancer Research, Association pour la Recherche sur le Cancer (ARC PJA 20151203149), A*MIDEX (ANR-11-IDEX-0001-02), Plan Cancer 2015 (C15076AS), PlBio-INCA, and Equipe Labelisée Ligue contre le Cancer.
• dc.format.mimetype application/pdf
• dc.identifier.citation Cieslak A, Charbonnier G, Tesio M, Mathieu EL, Belhocine M, Touzart A et al. Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation. J Exp Med. 2020; 217(9):e20192360. DOI: 10.1084/jem.20192360
• dc.identifier.doi http://dx.doi.org/10.1084/jem.20192360
• dc.identifier.issn 0022-1007
• dc.identifier.uri http://hdl.handle.net/10230/45880
• dc.language.iso eng
• dc.publisher Rockefeller University Press
• dc.relation.ispartof J Exp Med. 2020; 217(9):e20192360
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/282510
• dc.rights © 2020 Cieslak et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by-nc-sa/4.0/
• dc.subject.keyword Hematopoiesis
• dc.subject.keyword Leukemia
• dc.subject.keyword Lymphoma
• dc.title Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion