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

Agata Cieslak 1 Guillaume Charbonnier 2 Melania Tesio 1 Eve-Lyne Mathieu 2 Mohamed Belhocine 2 Aurore Touzart 1 Charlotte Smith 1 Guillaume Hypolite 1 Guillaume Andrieu 1 Joost H.A. Martens 3 Eva Janssen-Megens 3 Marta Gut 4 Ivo Gut 4 Nicolas Boissel 5 Arnaud Petit 6 Denis Puthier 2 Elizabeth Macintyre 1 Hendrik Stunnenberg 3 Salvatore Spicuglia 2 Vahid Asnafi 1
1 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
2 TAGC - Theories and Approaches of Genomic Complexity
3 Radboud university [Nijmegen]
4 UPF - Universitat Pompeu Fabra [Barcelona]
5 CHU Saint Louis [APHP]
6 AP-HP - Hôpital Armand Trousseau [AP-HP]
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
Keywords : Hematopoiesis Leukemia & Lymphoma
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Agata Cieslak, Guillaume Charbonnier, Melania Tesio, Eve-Lyne Mathieu, Mohamed Belhocine, et al.. Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation. Journal of Experimental Medicine, Rockefeller University Press, 2020, 217 (9), ⟨10.1084/jem.20192360⟩. ⟨hal-03015052⟩

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