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Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPIT (PU.1)
CALTECH, CA 91125 USA; Lund Univ, Sweden.
CALTECH, CA 91125 USA.
CALTECH, CA 91125 USA.
Lund Univ, Sweden.
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2018 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 28, no 10, p. 1508-1519Article in journal (Refereed) Published
Abstract [en]

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 down-regulated. 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-offunction 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 trade-offs for occupancy between site sequence quality and stage-dependent site accessibility in chromatin. At nonpromoter 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.

Place, publisher, year, edition, pages
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT , 2018. Vol. 28, no 10, p. 1508-1519
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-152077DOI: 10.1101/gr.231423.117ISI: 000446043800007PubMedID: 30171019OAI: oai:DiVA.org:liu-152077DiVA, id: diva2:1258309
Note

Funding Agencies|Swedish Research Council; Manpei Suzuki Diabetes Foundation; US Public Health Service [R01HD076915, R01AI95943]; L. A. Garfinkle Memorial Laboratory Fund; Al Sherman Foundation; Beckman Institute at Caltech; Albert Billings Ruddock Professorship

Available from: 2018-10-24 Created: 2018-10-24 Last updated: 2019-02-21

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