Excited to share the latest from the @MarsonLab! An investigation of context-specific gene regulation in T cells, which led to dynamic mechanisms required to control T cell rest and activation. Published today in @Nature thanks to the work of many!.

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Excited to share that the Arce Lab is launching today at @arcinstitute !.We will explore the mechanisms controlling immune cell function using genomics and biochemistry in an effort to understand immune-mediated diseases.

RT @MinetoOta: Thank you Jonathan for the elegant explanation of our recent work!. We dove into how we can model the gene regulatory archit….

RT @ImmunoSketch: Think of a conductor guiding an orchestra—scientists discovered how T cells fine-tune their responses to keep the immune….

RT @GladstoneInst: A team of scientists uncovered how one protein controls the behavior of immune cells, which could have applications for….

Comprehensively, this work revealed dynamic regulatory mechanisms that enable state-specific gene expression in T cells. This story was made possible by members of the Marson lab as well as exciting collaborations with @KroganLab @Satpathology and @jkpritch !.

Finally, we found that despite blunted activation responses, MED12 ablated cells had increased durability. T cells without MED12 were resistant to activation induced cell death, undergoing limited levels of apoptosis relative to control cells following stimulation.

To dissect this mechanism, we performed IP-MS to identify MED12 interaction partners. In addition to Mediator, many subunits of SETD1A/COMPASS, which deposits H3K4me1-3, were enriched. MED12 KO resulted in targeted loss of H3K4me3 and gene expression of several key regulators.

MED12 was upstream of numerous regulators in both networks, coordinating T cell rest and activation circuits. Using bulk RNASeq, we found that MED12 was enriched upstream of regulators of IL2RA and MED12 KO affected expression of state and activation-specific regulators.

We then created state-specific gene regulatory networks. Regulators that promote rest formed many positive connections, with convergence on key rest maintenance factors like KLF2. After stimulation, rest maintenance factor expression was reduced by activation promoting factors.

With CRISPRi Perturb-seq, we targeted regulators of IL2RA and assessed changes to the overall activation state in resting and stimulated cells. Many knockdowns had altered activation states and MED12 had opposite effects across conditions and was required for rest and activation.

Next, we turned to examine broader regulation of T cell activation states. IL2RA is a marker of T cell activation due to increased expression after stimulation. Because of this, we suspected that many of the identified regulators affect the overall cell activation state.

Using arrayed assays, we characterized the discrete windows of time after stimulation that select regulators functioned. Regulator effects were particularly dynamic in effector T cells, which express low IL2RA at rest but upregulate it to very high levels during activation.

The majority of IL2RA screen hits were cell type or activation state-specific. Surprisingly, several regulators had opposite effects across states including MED12, a standout subunit of the Mediator complex.

IL2RA, part of the IL-2 receptor, is differentially expressed between regulatory T cells (anti-inflammatory) and effector T cells (pro-inflammatory) and across activation states. Using CRISPR KO screens, we identified trans-regulators that control IL2RA across these contexts.

The T cell compartment contains diverse cell subsets that perform distinct roles but often rely on shared external signals to coordinate their activity. We wanted to better understand how gene expression is controlled across cell subsets and activation states by trans-regulators.

RT @J__Stock: Thrilled to share our work on inferring gene networks in T cells using CRISPR perturbations. We show how to build these netwo….