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Runx3 pioneers chromatin accessibility of cis-regulatory landscapes that drive memory CTL formation

ABSTRACT: T cell receptor (TCR) stimulation of naïve CD8+ T cells initiates reprogramming of cis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naïve cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 controls de novo access to memory CTL-specific cistromes prior to the first cell division, and is essential for memory CTL differentiation. Runx3 specifically promotes accessibility of cis-acting regions highly enriched with IRF, bZIP and Prdm1-like family TF motifs, upregulates IRF4 and establishes feed-forward transcriptional circuits that induce fundamental CTL attributes in memory precursor cells. Runx3 drives uncoupling from the naïve cell state, but subsequently restrains terminal differentiation of nascent CTL by preventing high expression of the TF T-bet and slowing effector cell proliferation. Enforced Runx3 expression enhances memory CTL differentiation and increases their numbers during iterative infections. Thus, Runx3 functions in a pioneering role to initialize and then ensure memory CTL differentiate. This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE111149 | GEO | 2018/04/19

REPOSITORIES: GEO

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Project description:T cell receptor (TCR) stimulation of naïve CD8+ T cells initiates reprogramming of cis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naïve cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 controls de novo access to memory CTL-specific cistromes prior to the first cell division, and is essential for memory CTL differentiation. Runx3 specifically promotes accessibility of cis-acting regions highly enriched with IRF, bZIP and Prdm1-like family TF motifs, upregulates IRF4 and establishes feed-forward transcriptional circuits that induce fundamental CTL attributes in memory precursor cells. Runx3 drives uncoupling from the naïve cell state, but subsequently restrains terminal differentiation of nascent CTL by preventing high expression of the TF T-bet and slowing effector cell proliferation. Enforced Runx3 expression enhances memory CTL differentiation and increases their numbers during iterative infections. Thus, Runx3 functions in a pioneering role to initialize and then ensure memory CTL differentiate.

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