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

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 down-regulated during T lineage commitment. The transcription factors Runx1 and GATA3 have been implicated in this Spi1 repression,...

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Autores principales: Hosokawa, Hiroyuki, Koizumi, Maria, Masuhara, Kaori, Romero-Wolf, Maile, Tanaka, Tomoaki, Nakayama, Toshinori, Rothenberg, Ellen V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241539/
https://www.ncbi.nlm.nih.gov/pubmed/34180951
http://dx.doi.org/10.1084/jem.20202648
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author Hosokawa, Hiroyuki
Koizumi, Maria
Masuhara, Kaori
Romero-Wolf, Maile
Tanaka, Tomoaki
Nakayama, Toshinori
Rothenberg, Ellen V.
author_facet Hosokawa, Hiroyuki
Koizumi, Maria
Masuhara, Kaori
Romero-Wolf, Maile
Tanaka, Tomoaki
Nakayama, Toshinori
Rothenberg, Ellen V.
author_sort Hosokawa, Hiroyuki
collection PubMed
description 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 down-regulated during T lineage commitment. The 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 down-regulates Spi1 expression in pro–T cells, while deletion of these factors after Spi1 down-regulation 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.
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spelling pubmed-82415392022-02-02 Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro–T cells Hosokawa, Hiroyuki Koizumi, Maria Masuhara, Kaori Romero-Wolf, Maile Tanaka, Tomoaki Nakayama, Toshinori Rothenberg, Ellen V. J Exp Med Article 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 down-regulated during T lineage commitment. The 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 down-regulates Spi1 expression in pro–T cells, while deletion of these factors after Spi1 down-regulation 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. Rockefeller University Press 2021-06-28 /pmc/articles/PMC8241539/ /pubmed/34180951 http://dx.doi.org/10.1084/jem.20202648 Text en © 2021 Hosokawa et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Hosokawa, Hiroyuki
Koizumi, Maria
Masuhara, Kaori
Romero-Wolf, Maile
Tanaka, Tomoaki
Nakayama, Toshinori
Rothenberg, Ellen V.
Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro–T cells
title Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro–T cells
title_full Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro–T cells
title_fullStr Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro–T cells
title_full_unstemmed Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro–T cells
title_short Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro–T cells
title_sort stage-specific action of runx1 and gata3 controls silencing of pu.1 expression in mouse pro–t cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241539/
https://www.ncbi.nlm.nih.gov/pubmed/34180951
http://dx.doi.org/10.1084/jem.20202648
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