Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK; Department of Biosciences and Nutrition, Karolinska Institutet, Hälsovägen 7, Novum, SE-141 83, Huddinge, Sweden.
Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
Cell. 2019 Feb 7;176(4):882-896.e18. doi: 10.1016/j.cell.2018.11.044. Epub 2019 Jan 10.
T helper type 2 (Th2) cells are important regulators of mammalian adaptive immunity and have relevance for infection, autoimmunity, and tumor immunology. Using a newly developed, genome-wide retroviral CRISPR knockout (KO) library, combined with RNA-seq, ATAC-seq, and ChIP-seq, we have dissected the regulatory circuitry governing activation and differentiation of these cells. Our experiments distinguish cell activation versus differentiation in a quantitative framework. We demonstrate that these two processes are tightly coupled and are jointly controlled by many transcription factors, metabolic genes, and cytokine/receptor pairs. There are only a small number of genes regulating differentiation without any role in activation. By combining biochemical and genetic data, we provide an atlas for Th2 differentiation, validating known regulators and identifying factors, such as Pparg and Bhlhe40, as part of the core regulatory network governing Th2 helper cell fates.
T 辅助细胞 2（Th2）是哺乳动物适应性免疫的重要调节因子，与感染、自身免疫和肿瘤免疫学有关。使用新开发的全基因组逆转录病毒 CRISPR 敲除（KO）文库，结合 RNA-seq、ATAC-seq 和 ChIP-seq，我们已经解析了调节这些细胞激活和分化的调控回路。我们的实验在定量框架中区分了细胞激活与分化。我们证明这两个过程紧密耦合，由许多转录因子、代谢基因和细胞因子/受体对共同控制。只有少数基因在不影响激活的情况下调节分化。通过结合生化和遗传数据，我们提供了 Th2 分化的图谱，验证了已知的调节剂，并确定了 Pparg 和 Bhlhe40 等因子作为调节 Th2 辅助细胞命运的核心调控网络的一部分。
