Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification.
Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification.
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E 蛋白 TCF4 控制树突状细胞谱系规范的异构体特异性表达和反馈调节。
DOI：
10.1016/j.immuni.2016.11.006
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发表时间：
2017-01-17
期刊：
影响因子：
32.4
通讯作者：
Reizis B
中科院分区：
文献类型：
--
作者：
Grajkowska LT;Ceribelli M;Lau CM;Warren ME;Tiniakou I;Nakandakari Higa S;Bunin A;Haecker H;Mirny LA;Staudt LM;Reizis B
产生干扰素的浆细胞样DC （pDC）和抗原呈递型DC （cDC）之间的细胞命运决定是由E蛋白转录因子TCF4 （E2-2）控制的。我们报道TCF4包含两个转录异构体，它们都是体外最佳pDC发育所必需的。Tcf4长异构体在pDCs中特异性表达，其在小鼠中的缺失会损害pDCs的发育并导致非典型CD8+ cDCs的扩增。Tcf4的表达始于祖细胞，并在pDCs中进一步上调，与多个增强子元件的阶段特异性活性相关。在pDC分化过程中，Tcf4的下游需要一个保守的增强子进行上调，这揭示了一个正反馈回路。Tcf4的表达和由此产生的pDC分化对增强子结合BET蛋白活性的抑制具有选择性敏感性。因此，谱系特异性异构体表达和通过远端调控元件的β依赖反馈调控促进了E蛋白的谱系指定功能。浆细胞样树突状细胞的发育由E蛋白转录因子TCF4 （E2-2）驱动。Grajkowska等研究表明，TCF4本身受多种机制控制，包括亚型特异性表达和通过远端调控元件的正反馈调控。
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. 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.