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

authors

Cieslak Agata
Charbonnier Guillaume
Tesio Melania
Mathieu Eve-Lyne
Belhocine Mohamed
Touzart Aurore
Smith Charlotte
Hypolite Guillaume
Andrieu Guillaume
Martens Joost H.A.
Janssen-Megens Eva
Gut Marta
Gut Ivo
Boissel Nicolas
Petit Arnaud
Puthier Denis
Macintyre Elizabeth
Stunnenberg Hendrik
Spicuglia Salvatore
Asnafi Vahid

keywords

Hematopoiesis
Leukemia & Lymphoma

document type

ART

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

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