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

• Published in: Immunity (Cambridge, Mass.) Vol. 46; no. 1; pp. 65 - 77
• Main Authors: Grajkowska, Lucja T., Ceribelli, Michele, Lau, Colleen M., Warren, Margaret E., Tiniakou, Ioanna, Nakandakari Higa, Sandra, Bunin, Anna, Haecker, Hans, Mirny, Leonid A., Staudt, Louis M., Reizis, Boris
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.01.2017; Elsevier Limited
• Subjects: Animals; Antigens; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - immunology; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Bet protein; CD8 antigen; Cell Differentiation - immunology; Cell fate; Cell Lineage; Chromatin Immunoprecipitation; Control theory; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - immunology; Deoxyribonucleic acid; Differentiation; DNA; E protein; E proteins; enhancers; Feedback; Feedback loops; feedback regulation; Flow Cytometry; Gene expression; Gene Expression Profiling; Interferon; Isoforms; Mice; Mice, Inbred C57BL; Mice, Knockout; plasmacytoid dendritic cells; Positive feedback; Protein Isoforms - immunology; Protein Isoforms - metabolism; Proteins; Regulatory sequences; Rodents; Transcription Factor 4; Transcription factors; Transcriptome; plasmacytoid dendritic cells; dendritic cells; E proteins; enhancers; feedback regulation; transcription factors
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.11.006

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. [Display omitted] •Two functional isoforms of the E protein factor TCF4 (E2-2) are expressed in pDCs•The “long” TCF4 isoform is pDC specific and controls pDC development in vivo•A conserved enhancer controls TCF4 expression and pDC development•TCF4 expression and pDC development are sensitive to BET protein inhibitors The development of plasmacytoid dendritic cells is driven by E protein transcription factor TCF4 (E2-2). Grajkowska et al. show that TCF4 itself is controlled by multiple mechanisms including isoform-specific expression and positive feedback regulation through distal regulatory elements.