title: Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification.
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.
authors.affiliation: 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.
authors.forename: Lucja T
authors.initials: LT
authors.lastname: Grajkowska
authors.affiliation: 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.
authors.forename: Michele
authors.initials: M
authors.lastname: Ceribelli
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Lau
authors.affiliation: 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.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Warren
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Tiniakou
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Nakandakari Higa
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Bunin
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Haecker
authors.affiliation: Department of Physics and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Leonid A
authors.initials: LA
authors.lastname: Mirny
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.affiliation: 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.
authors.forename: Boris
authors.initials: B
authors.lastname: Reizis
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage; D047369:Chromatin Immunoprecipitation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000276:immunology / Q000378:metabolism; D000073940:Transcription Factor 4; D059467:Transcriptome
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D020033:Protein Isoforms; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4
keywords: E proteins; dendritic cells; enhancers; feedback regulation; plasmacytoid dendritic cells; transcription factors