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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 (E\u03b1) is in an open and unmethylated chromatin structure well before activation. Integrative analyses revealed that the HOXA5-9 transcription factors repress the E\u03b1 enhancer at early stages of T cell differentiation, while their decommission is required for TCRA locus activation and enforced \u03b1\u03b2 T lineage differentiation. Remarkably, the HOXA-mediated repression of E\u03b1 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.<\/jats:p>","DOI":"10.1084\/jem.20192360","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T13:17:27Z","timestamp":1594819047000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":34,"title":["Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation"],"prefix":"10.1084","volume":"217","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1015-9448","authenticated-orcid":true,"given":"Agata","family":"Cieslak","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Paris (Descartes), Institut Necker-Enfants Malades, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U1151, and Laboratory of Onco-Hematology, Assistance Publique-H\u00f4pitaux de Paris, H\u00f4pital Necker 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