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Immunity. 2017 Jan 17;46(1):65-77. doi: 10.1016/j.immuni.2016.11.006. Epub 2016 Dec 13.

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification.

Author information

1
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
2
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
3
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
4
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Graduate Program in Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
5
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
6
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7
Department of Physics and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
8
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
9
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: boris.reizis@nyumc.org.

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.

KEYWORDS:

E proteins; dendritic cells; enhancers; feedback regulation; plasmacytoid dendritic cells; transcription factors

PMID:
27986456
PMCID:
PMC5243153
DOI:
10.1016/j.immuni.2016.11.006
[Indexed for MEDLINE]
Free PMC Article

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