Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU.1
- Author(s)
- Champhekar, A; Damle, SS; Freedman, G; Carotta, S; Nutt, SL; Rothenberg, EV;
- Details
- Publication Year 2015-04-15,Volume 29,Issue #8,Page 832-48
- Journal Title
- Genes Dev
- Publication Type
- Journal Article
- Abstract
- The ETS family transcription factor PU.1 is essential for the development of several blood lineages, including T cells, but its function in intrathymic T-cell precursors has been poorly defined. In the thymus, high PU.1 expression persists through multiple cell divisions in early stages but then falls sharply during T-cell lineage commitment. PU.1 silencing is critical for T-cell commitment, but it has remained unknown how PU.1 activities could contribute positively to T-cell development. Here we employed conditional knockout and modified antagonist PU.1 constructs to perturb PU.1 function stage-specifically in early T cells. We show that PU.1 is needed for full proliferation, restricting access to some non-T fates, and controlling the timing of T-cell developmental progression such that removal or antagonism of endogenous PU.1 allows precocious access to T-cell differentiation. Dominant-negative effects reveal that this repression by PU.1 is mediated indirectly. Genome-wide transcriptome analysis identifies novel targets of PU.1 positive and negative regulation affecting progenitor cell signaling and cell biology and indicating distinct regulatory effects on different subsets of progenitor cell transcription factors. Thus, in addition to supporting early T-cell proliferation, PU.1 regulates the timing of activation of the core T-lineage developmental program.
- Publisher
- CSHLP
- Research Division(s)
- Molecular Immunology
- PubMed ID
- 25846797
- Publisher's Version
- https://doi.org/10.1101/gad.259879.115
- NHMRC Grants
- NHMRC/1054925, NHMRC/1058238,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-05-20 10:11:19
Last Modified: 2016-04-20 12:06:23