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When lymphoid precursors undergo commitment to the T-cell program within the thymus, there are global rearrangements of chromatin states as well as sharp changes in the expression of a discrete set of transcription factors. Progenitor-associated regulatory genes like Spi1 (PU. 1) and Bcl11a turn off during commitment while definitive T-cell regulatory genes like Bcl11b, Lef1, and Ets1 turn on. A simple model would be that the newly expressed factors and the downregulated factors mutually repress each other and that the shift in global gene expression profiles reflects the direct target specificities and intrinsic positive or negative regulatory activities of each of these factors. However, when examined in depth, there are inconsistencies in going from the immediate target genes of each of these factors, as defined by ChIP-seq and acute perturbation experiments, to the much broader developmental shifts in global …