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Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1)

Ungerbäck, Jonas and Hosokawa, Hiroyuki and Wang, Xun and Strid, Tobias and Williams, Brian A. and Sigvardsson, Mikael and Rothenberg, Ellen V. (2018) Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1). Genome Research, 28 (10). pp. 1508-1519. ISSN 1088-9051. PMCID PMC6169891.

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SPI1 (also known as PU.1) is a dominant but transient regulator in early T-cell precursors and a potent transcriptional controller of developmentally important pro-T cell genes. Before T-lineage commitment, open chromatin is frequently occupied by PU.1, and many PU.1 sites lose accessibility when PU.1 is later downregulated. Pioneering activity of PU.1 was tested in this developmentally dynamic context, by quantitating the relationships between PU.1 occupancy and site quality and accessibility as PU.1 levels naturally declined in pro-T cell development, and by using stage-specific gain and loss of function perturbations to relate binding to effects on target genes. PU.1 could bind closed genomic sites, but rapidly opened many of them, despite the absence of its frequent collaborator, CEBPA. RUNX motifs and RUNX1 binding were often linked to PU.1 at open sites, but highly expressed PU.1 could bind its sites without RUNX1. The dynamic properties of PU.1 engagements implied that PU.1 binding affinity and concentration determine its occupancy choices, but with quantitative tradeoffs for occupancy between site sequence quality and stage-dependent site accessibility in chromatin. At non-promoter sites PU.1 binding criteria were more stringent than at promoters, and PU.1 was also much more effective as a transcriptional regulator at non-promoter sites where local chromatin accessibility depended on the presence of PU.1. Notably, closed chromatin presented a qualitative barrier to occupancy by the PU.1 DNA binding domain alone. Thus, effective pioneering at closed chromatin sites also depends on requirements beyond site recognition served by non-DNA binding domains of PU.1.

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URLURL TypeDescription CentralArticle Paper
Hosokawa, Hiroyuki0000-0002-9592-2889
Rothenberg, Ellen V.0000-0002-3901-347X
Alternate Title:Pioneering and gene control by PU.1 in pro-T cells
Additional Information:© 2018 Published by Cold Spring Harbor Laboratory Press. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at Received October 18, 2017; Accepted August 30, 2018; Published in Advance August 31, 2018. We thank Jeffrey Longmate (Beckman Research Institute of the City of Hope), Hao Yuan Kueh (Caltech and University of Washington), and Barbara Wold (Caltech) for generous advice; Rothenberg group members and previous group members, Marissa Del Real (City of Hope) and Ameya Champhekar (UCLA), for constructs and helpful discussion; Diana Perez, Jaime Tijerina, and Rochelle Diamond for cell sorting and advice; Ingrid Soto for mouse colony care; Vijaya Kumar for library preparation and sequencing; Henry Amrhein and Diane Trout for computational system assistance; and Igor Antoshechkin for sequencing facility management. This research was supported by fellowships from the Swedish Research Council (to JU), from the Manpei Suzuki Diabetes Foundation (to HH), grants from the USPHS to EVR (R01HD076915, R01AI95943), by the L. A. Garfinkle Memorial Laboratory Fund and the Al Sherman Foundation, Facility and Resource Center support from the Beckman Institute at Caltech, and the Albert Billings Ruddock Professorship to EVR. None of the authors have any conflicts of interest to report.
Funding AgencyGrant Number
Swedish Research CouncilUNSPECIFIED
Manpei Suzuki Diabetes FoundationUNSPECIFIED
Louis A. Garfinkle Memorial Laboratory FundUNSPECIFIED
Al Sherman FoundationUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Albert Billings Ruddock ProfessorshipUNSPECIFIED
Subject Keywords:SPI1, DNA accessibility, T-cell development, distal regulatory elements, promoters, repression
Issue or Number:10
PubMed Central ID:PMC6169891
Record Number:CaltechAUTHORS:20180910-100610307
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Official Citation:Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) Jonas Ungerbäck, Hiroyuki Hosokawa, Xun Wang, Tobias Strid, Brian A. Williams, Mikael Sigvardsson, and Ellen V. Rothenberg Genome Res. October 2018 28: 1508-1519; Published in Advance August 31, 2018, doi:10.1101/gr.231423.117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:89481
Deposited By: Tony Diaz
Deposited On:10 Sep 2018 18:05
Last Modified:05 Nov 2019 19:20

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