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Cell-Type-Specific Activation and Repression of PU.1 by a Complex of Discrete, Functionally Specialized cis-Regulatory Elements

Zarnegar, Mark A. and Chen, Jing and Rothenberg, Ellen V. (2010) Cell-Type-Specific Activation and Repression of PU.1 by a Complex of Discrete, Functionally Specialized cis-Regulatory Elements. Molecular and Cellular Biology, 30 (20). pp. 4922-1939. ISSN 0270-7306. PMCID PMC2950536.

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The transcription factor PU.1 is critical for multiple hematopoietic lineages, but different leukocyte types require strictly distinct patterns of PU.1 regulation. PU.1 is required early for T-cell lineage development but then must be repressed by a stage-specific mechanism correlated with commitment. Other lineages require steady, low expression or upregulation. Until now, only the promoter plus a distal upstream regulatory element (URE) could be invoked to explain nearly all Sfpi1 (PU.1) activation and repression, including bifunctional effects of Runx1. However, the URE is dispensable for most Sfpi1 downregulation in early T cells, and we show that it retains enhancer activity in immature T-lineage cells even where endogenous Sfpi1 is repressed. We now present evidence for another complex of conserved noncoding elements that mediate discrete, cell-type-specific regulatory features of Sfpi1, including a myeloid cell-specific activating element and a separate, pro-T-cell-specific silencer element. These elements yield opposite, cell-type-specific responses to Runx1. T-cell-specific repression requires Runx1 acting through multiple nonconsensus sites in the silencer core. These newly characterized sites recruit Runx1 binding in early T cells in vivo and define a functionally specific scaffold for dose-dependent, Runx-mediated repression.

Item Type:Article
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URLURL TypeDescription CentralArticle
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2010 American Society for Microbiology. Received 25 March 2010; Returned for modification 3 May 2010; Accepted 29 July 2010. We are grateful to Masanobu Satake (Tohoku University, Sendai, Japan) for donating pan-Runx antibody and to Janice Telfer (University of Massachusetts, Amherst, MA) for the Runx1 DN construct. We also thank Jingli Zhang and Georgi Marinov for sharing data before publication and Rochelle Diamond for help in isolating primary mouse tissues and excellent lab management. This work was supported by grants from the U.S. PHS, R21 DK073658 and R01 CA90233, and by funds from the Louis A. Garfinkle Memorial Laboratory Fund, the Al Sherman Foundation, and the Albert Billings Ruddock Professorship to E.V.R.
Funding AgencyGrant Number
NIHR21 DK073658
NIHR01 CA90233
Louis A. Garfinkle Memorial Laboratory FundUNSPECIFIED
Al Sherman FoundationUNSPECIFIED
Albert Billings Ruddock ProfessorshipUNSPECIFIED
Issue or Number:20
PubMed Central ID:PMC2950536
Record Number:CaltechAUTHORS:20100927-104747466
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:20156
Deposited By: Jason Perez
Deposited On:27 Sep 2010 22:54
Last Modified:03 Oct 2019 02:06

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