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

The Journal of Experimental Medicine
Agata CieslakVahid Asnafi

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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Citations

Feb 10, 2021·Blood Advances·Nabih MaslahGuillaume P Andrieu
Nov 15, 2020·International Journal of Molecular Sciences·Alonso Rodríguez-CaparrósCristina Hernández-Munain
Apr 17, 2021·Trends in Immunology·Laura BelverAdolfo A Ferrando

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Methods Mentioned

BETA
immunoprecipitation
ChIP-seq
WGBS
RNA-seq
acetylation
BS-seq
ChIP
PCR
Low-Density
transfection

Clinical Trials Mentioned

NCT00222027
NCT00327678

Software Mentioned

GREAT
rGREAT R
ChromHMM
crossmap
Chromdet
bowtie2
IGV
EdgeR
ImageJ
FactoMineR R package

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