Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification
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Author(s)
Grajkowska, Lucja T.
Ceribelli, Michele
Lau, Colleen M.
Warren, Margaret E.
Tiniakou, Ioanna
Nakandakari Higa, Sandra
Bunin, Anna
Haecker, Hans
Staudt, Louis M.
Reizis, Boris
Date Issued
December 2016
Journal
Immunity
Publisher
Elsevier
Citation
Grajkowska, Lucja T. et al. “Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification.” Immunity 46, 1 (January 2017): 65–77 © 2017 Elsevier Inc
Version
Author's final manuscript
Abstract
The cell fate decision between interferon-producing plasmacytoid DC (pDC) and antigen-presenting classical DC (cDC) is controlled by the E protein transcription factor TCF4 (E2-2). We report that TCF4 comprises two transcriptional isoforms, both of which are required for optimal pDC development in vitro. The long Tcf4 isoform is expressed specifically in pDCs, and its deletion in mice impaired pDCs development and led to the expansion of non-canonical CD8⁺ cDCs. The expression of Tcf4 commenced in progenitors and was further upregulated in pDCs, correlating with stage-specific activity of multiple enhancer elements. A conserved enhancer downstream of Tcf4 was required for its upregulation during pDC differentiation, revealing a positive feedback loop. The expression of Tcf4 and the resulting pDC differentiation were selectively sensitive to the inhibition of enhancer-binding BET protein activity. Thus, lineage-specifying function of E proteins is facilitated by lineage-specific isoform expression and by BET-dependent feedback regulation through distal regulatory elements.
MIT Department
Institute for Medical Engineering and Science
Massachusetts Institute of Technology. Department of Physics
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.IMMUNI.2016.11.006
