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Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development

Rothenberg, Ellen V. and Hosokawa, Hiroyuki and Ungerbäck, Jonas (2019) Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development. Frontiers in Immunology, 10 . Art. No. 228. ISSN 1664-3224.

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PU.1 is an ETS-family transcription factor that plays a broad range of roles in hematopoiesis. A direct regulator of myeloid, dendritic-cell, and B cell functional programs, and a well-known antagonist of terminal erythroid cell differentiation, it is also expressed in the earliest stages of T-cell development of each cohort of intrathymic pro-T cells. Its expression in this context appears to give T-cell precursors initial, transient access to myeloid and dendritic cell developmental competence and therefore to represent a source of antagonism or delay of T-cell lineage commitment. However, it has remained uncertain until recently why T-cell development is also intensely dependent upon PU.1. Here, we review recent work that sheds light on the molecular biology of PU.1 action across the genome in pro-T cells and identifies the genes that depend on PU.1 for their correct regulation. This work indicates modes of chromatin engagement, pioneering, and cofactor recruitment (“coregulator theft”) by PU.1 as well as gene network interactions that not only affect specific target genes but also have system-wide regulatory consequences, amplifying the impact of PU.1 beyond its own direct binding targets. The genes directly regulated by PU.1 also suggest a far-reaching transformation of cell biology and signaling potential between the early stages of T-cell development when PU.1 is expressed and when it is silenced. These cell-biological functions can be important to distinguish fetal from adult T-cell development and have the potential to illuminate aspects of thymic function that have so far remained the most mysterious.

Item Type:Article
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Rothenberg, Ellen V.0000-0002-3901-347X
Hosokawa, Hiroyuki0000-0002-9592-2889
Additional Information:© 2019 Rothenberg, Hosokawa and Ungerbäck. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Received: 23 November 2018; Accepted: 28 January 2019; Published: 20 February 2019. We thank members of the Rothenberg lab and members of the laboratories of Mikael Sigvardsson, Tomoaki Tanaka, and Barbara Wold for stimulating discussions. The authors' own research on this subject was supported by fellowships from the Swedish Research Council (JU) and the Manpei Suzuki Diabetes Foundation (HH), by grants from the USPHS, R01AI095943 and R01HD076915 (ER), and by the Albert Billings Ruddock Professorship (ER). Author Contributions: ER wrote the paper, contributed to ideas in the review, and directed research that led to this review. HH and JU carried out research that led to this review, contributed to ideas in the review, provided some figures and edited the paper. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding AgencyGrant Number
Swedish Research CouncilUNSPECIFIED
Manpei Suzuki Diabetes FoundationUNSPECIFIED
Albert Billings Ruddock ProfessorshipUNSPECIFIED
Subject Keywords:transcription factor, developmental gene regulation, chromatin, T lymphocyte development, thymus, gene network, cell signaling, hematopoiesis
Record Number:CaltechAUTHORS:20190228-144651277
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Official Citation:Rothenberg EV, Hosokawa H and Ungerbäck J (2019) Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development. Front. Immunol. 10:228. doi: 10.3389/fimmu.2019.00228
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:93361
Deposited By: Tony Diaz
Deposited On:28 Feb 2019 23:05
Last Modified:28 Feb 2019 23:05

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