Transcriptional and epigenetic thresholds for entry to the T-cell developmental program

Abstract

The T-cell development program is induced in hematopoietic progenitors by encounter with Notch ligands in the thymus. It is known that T-lineage transcription factors, TCF-1 (encoded by Tcf7) and GATA-3, are activated during the early stages of the response. With the activation of GATA-3, the cells lose access to the B-cell fate alternative. However, the cells still maintain a program of progenitor-associated gene expression including Tal1, Sfpi1, Hhex, Bcl11a, Gfi1b, Lyl1, and others. The cells expressing these progenitor-associated genes still appear to be uncommitted to the T-cell fate and include many that retain conditional access to nonlymphoid alternatives including dendritic cell and Gr-1+ Mac-1+ myeloid cell differentiation. The cells only become committed as they turn on another wave of T-cell genes, including the lineage-specific transcription factor Bcl11b. The individual steps in this process are slow, requiring multiple cell cycles per transition. Transcriptional perturbation, genomic analysis, and live-cell imaging experiments shed light on the staging of individual transitions in the process as well as the rate-limiting steps that yield the slow overall pace. We will present evidence for three specific regulatory thresholds that the cells must overcome: an initial PU.1-restricted threshold for the activation of definitive T-cell genes by Notch signals; a separate threshold, partly dependent on GATA-3, for the silencing of PU.1; and yet another, epigenetically controlled threshold for the activation of Bcl11b. The separation of these steps permits the system to adapt to radically different kinetic regimes in fetal and adult T-cell generation.

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