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Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro-T cells

ABSTRACT: PU.1 (encoded by Spi1), an ETS-family transcription factor with many hematopoietic roles, is highly expressed in the earliest intrathymic T cell progenitors but must be downregulated during T-lineage commitment. Transcription factors Runx1 and GATA3 have been implicated in this Spi1 repression, but the basis of the timing was unknown. We show that increasing Runx1 and/or GATA3 downregulates Spi1 expression in pro-T cells, while deletion of these factors after Spi1 downregulation reactivates its expression. Leveraging the stage-specificities of repression and transcription factor binding revealed an unconventional but functional site in Spi1 intron 2. Acute Cas9-mediated deletion or disruption of the Runx and GATA motifs in this element reactivates silenced Spi1 expression in a pro-T cell line, substantially more than disruption of other candidate elements, and counteracts the repression of Spi1 in primary pro-T cells during commitment. Thus, Runx1 and GATA3 work stage-specifically through an intronic silencing element in mouse Spi1 to control strength and maintenance of Spi1 repression during T-lineage commitment.

ORGANISM(S): Mus musculus

PROVIDER: GSE159960 | GEO | 2021/06/13

REPOSITORIES: GEO

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