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Genome-wide CRISPR screens in T helper cells reveal pervasive cross-talk between activation and differentiation

By Johan Henriksson, Xi Chen, Tomás Gomes, Ubaid Ullah, K.B. Meyer, Ricardo Miragaia, Graham Duddy, Jhuma Pramanik, Kosuke Yusa, Riitta Lahesmaa, Sarah A. Teichmann

Posted 04 Oct 2017
bioRxiv DOI: 10.1101/196022

T helper type 2 (Th2) cells are important regulators of mammalian adaptive immunity and have relevance for infection, auto-immunity and tumour immunology. Using a newly developed, genome-wide retroviral CRISPR knock-out (KO) library, combined with RNA-seq, ATAC-seq and ChIP-seq, we have dissected the regulatory circuitry governing activation (including proliferation) 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 is only a small number of genes regulating differentiation without any role in activation. Our study provides an atlas for the T helper cell regulatory network, pinpointing key players of Th2 differentiation and demonstrating remarkable plasticity between the diverse T helper cell fates. We provide an online resource for interactive data querying at: http://data.teichlab.org.

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