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Published August 8, 2013 | Supplemental Material + Published
Journal Article Open

A far downstream enhancer for murine Bcl11b controls its T-cell specific expression

Abstract

Bcl11b is a T-cell specific gene in hematopoiesis that begins expression during T-lineage commitment and is required for this process. Aberrant expression of BCL11B or proto-oncogene translocation to the vicinity of BCL11B can be a contributing factor in human T-ALL. To identify the mechanism that controls its distinctive T-lineage expression, we corrected the identified Bcl11b transcription start site and mapped a cell-type–specific differentially methylated region bracketing the Bcl11b promoter. We identified a 1.9-kb region 850 kb downstream of Bcl11b, "Major Peak," distinguished by its dynamic histone marking pattern in development that mirrors the pattern at the Bcl11b promoter. Looping interactions between promoter-proximal elements including the differentially methylated region and downstream elements in the Major Peak are required to recapitulate the T-cell specific expression of Bcl11b in stable reporter assays. Functional dissection of the Major Peak sequence showed distinct subregions, in which TCF-1 sites and a conserved element were required for T-lineage–specific activation and silencing in non-T cells. A bacterial artificial chromosome encompassing the full Bcl11b gene still required the addition of the Major Peak to exhibit T-cell specific expression. Thus, promoter-proximal and Major Peak sequences are cis-regulatory elements that interact over 850 kb to control expression of Bcl11b in hematopoietic cells.

Additional Information

© 2013 by The American Society of Hematology. Submitted August 2, 2012; accepted May 17, 2013. Prepublished online as Blood First Edition paper, June 5, 2013. The authors thank Mark A. Zarnegar and members of the Rothenberg laboratory for helpful discussions and for sharing data before publication. This work was supported by a California Institute for Regenerative Medicine fellowship (L.L.), National Institutes of Health grants R33HL089123, RC2CA148278, R01AI095943 (E.V.R.), and R21 AI076720 (F.G.), by American Cancer Society/Research Scholar Grants, LIB-113428 (F.G.), and the Louis A. Garfinkle Memorial Laboratory Fund, the Al Sherman Foundation, and the Albert Billings Ruddock Professorship (E.V.R.). Authorship: Contribution: L.L. designed and performed research, analyzed data, and wrote the paper; J.A.Z. analyzed data; M.D. performed research and analyzed data; H.Y.K. and R.M. contributed new reagents; F.G. analyzed data; and E.V.R. designed research, analyzed data, and wrote the paper. Conflict-of-interest disclosure: The authors declare no competing financial interests. The current affiliation for J.A.Z. is Genentech, South San Francisco, CA. The current affiliation for M.D. is Laboratory of Molecular Immunogenomics, Genomics and Immunity Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734.

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Published - Blood-2013-Li-902-11.pdf

Supplemental Material - Document1.pdf

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Created:
August 19, 2023
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October 24, 2023