Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification
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 v...
| Main Authors: | , , , , , , , , , , |
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Elsevier
2018
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| Online Access: | http://hdl.handle.net/1721.1/113710 https://orcid.org/0000-0002-0785-5410 |
| _version_ | 1826191166322769920 |
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| author | 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 Mirny, Leonid A |
| author2 | Institute for Medical Engineering and Science |
| author_facet | Institute for Medical Engineering and Science 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 Mirny, Leonid A |
| author_sort | Grajkowska, Lucja T. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:51:20Z |
| format | Article |
| id | mit-1721.1/113710 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T08:51:20Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1137102022-09-26T08:48:49Z Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification 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 Mirny, Leonid A Institute for Medical Engineering and Science Massachusetts Institute of Technology. Department of Physics Mirny, Leonid A 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. 2018-02-16T16:52:15Z 2018-02-16T16:52:15Z 2016-12 2018-02-13T15:22:11Z Article http://purl.org/eprint/type/JournalArticle 1074-7613 1097-4180 http://hdl.handle.net/1721.1/113710 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 https://orcid.org/0000-0002-0785-5410 http://dx.doi.org/10.1016/J.IMMUNI.2016.11.006 Immunity Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | 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 Mirny, Leonid A Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification |
| title | Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification |
| title_full | Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification |
| title_fullStr | Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification |
| title_full_unstemmed | Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification |
| title_short | Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification |
| title_sort | isoform specific expression and feedback regulation of e protein tcf4 control dendritic cell lineage specification |
| url | http://hdl.handle.net/1721.1/113710 https://orcid.org/0000-0002-0785-5410 |
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