Comparison of gene expression profiles of naïve and in vitro effector CD8+ T cells from wild-type and BATF-/- mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE54215 | GEO | 2014/03/02
SECONDARY ACCESSION(S): PRJNA235928
REPOSITORIES: GEO
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Project description:The transcription factor BATF is required for Th17 and TFH differentiation. Here, we show that BATF also has a fundamental role in regulating effector CD8+ T cell differentiation. BATF-deficient CD8+ T cells show profound defects in effector expansion and undergo proliferative and metabolic catastrophe early after antigen encounter. BATF, together with IRF4 and Jun proteins, binds to and promotes early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors, while paradoxically repressing genes encoding effector molecules (IFNg and granzyme B). Thus, BATF amplifies TCR-dependent transcription factor expression and augments inflammatory signal propagation but restrains effector gene expression. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved. P14 TCR transgenic CD8+ T cells from wild-type or BATF-/- mice were examined either as naïve cells or after 3 days of in vitro stimulation with antibodies to CD3 and CD28 in the presence of IL-2
2014-03-02 | E-GEOD-54215 | biostudies-arrayexpress
Project description:The transcription factor BATF is required for Th17 and TFH differentiation. Here, we show that BATF also has a fundamental role in regulating effector CD8+ T cell differentiation. BATF-deficient CD8+ T cells show profound defects in effector expansion and undergo proliferative and metabolic catastrophe early after antigen encounter. BATF, together with IRF4 and Jun proteins, binds to and promotes early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors, while paradoxically repressing genes encoding effector molecules (IFNg and granzyme B). Thus, BATF amplifies TCR-dependent transcription factor expression and augments inflammatory signal propagation but restrains effector gene expression. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved. This is an examination of 5 different transcription factors (TFs) with 5 different histone modifications in effector CD8+ T cells. Two of the TFs (BATF and IRF4) and the histone modifications were replicated. Appropriate control sequence files for ChIP input, IgG ChIP, and Total H3 are also included.
2014-03-02 | E-GEOD-54191 | biostudies-arrayexpress
Project description:The transcription factor BATF is required for Th17 and TFH differentiation. Here, we show that BATF also has a fundamental role in regulating effector CD8+ T cell differentiation. BATF-deficient CD8+ T cells show profound defects in effector expansion and undergo proliferative and metabolic catastrophe early after antigen encounter. BATF, together with IRF4 and Jun proteins, binds to and promotes early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors, while paradoxically repressing genes encoding effector molecules (IFNg and granzyme B). Thus, BATF amplifies TCR-dependent transcription factor expression and augments inflammatory signal propagation but restrains effector gene expression. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved.
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Project description:The response of naive CD8+ T cells to their cognate antigen involves rapid and broad changes in gene expression that are coupled with extensive chromatin remodeling, but the mechanisms governing these changes are not fully understood. In this study, we investigated how this process depends on the activity of the basic leucine zipper ATF-like transcription factor Batf, which is essential for the earliest phase of effector CD8+ T cell differentiation. Through genome scale profiling of multiple modalities, we characterized the role of Batf in chromatin organization at several levels, including the accessibility of key regulatory regions, the expression of nearby genes, and the interactions these regions make with each other and with key transcription factors. We quantified the dependencies between Batf and other transcription factors and identified a core transcription factor network that cooperated with Batf, including Irf4, and the transcription factors Runx3 and T-bet, which tended to co-localize with Batf and bind in regions whose accessibility and long-range interactions were mediated by Batf. We functionally demonstrated the synergistic activity of this network in initiating aspects of the effector T cells’ transcriptional and chromatin accessibility profiles in an ectopically-induced fibroblast system. Using HiChIP, we further found that overexpressing all four factors in fibroblasts was required to recapitulate important aspects of the CD8+ T cell chromatin architecture. Our results provided a comprehensive resource for studying the epigenomic and transcriptomic landscape of effector differentiation of cytotoxic T cells and suggested various modes of dependencies between transcription factors in this process.
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Project description:The response of naive CD8+ T cells to their cognate antigen involves rapid and broad changes in gene expression that are coupled with extensive chromatin remodeling, but the mechanisms governing these changes are not fully understood. In this study, we investigated how this process depends on the activity of the basic leucine zipper ATF-like transcription factor Batf, which is essential for the earliest phase of effector CD8+ T cell differentiation. Through genome scale profiling of multiple modalities, we characterized the role of Batf in chromatin organization at several levels, including the accessibility of key regulatory regions, the expression of nearby genes, and the interactions these regions make with each other and with key transcription factors. We quantified the dependencies between Batf and other transcription factors and identified a core transcription factor network that cooperated with Batf, including Irf4, and the transcription factors Runx3 and T-bet, which tended to co-localize with Batf and bind in regions whose accessibility and long-range interactions were mediated by Batf. We functionally demonstrated the synergistic activity of this network in initiating aspects of the effector T cells’ transcriptional and chromatin accessibility profiles in an ectopically-induced fibroblast system. Using HiChIP, we further found that overexpressing all four factors in fibroblasts was required to recapitulate important aspects of the CD8+ T cell chromatin architecture. Our results provided a comprehensive resource for studying the epigenomic and transcriptomic landscape of effector differentiation of cytotoxic T cells and suggested various modes of dependencies between transcription factors in this process.
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