Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells
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ABSTRACT:
PROVIDER: PRJNA1000909 | ENA |
REPOSITORIES: ENA
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Project description:Human regulatory T cells (Tregs) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of Tregs for cancer therapy, without impacting immune homeostasis. Identifying pathways that may distinguish tumor-restricted Tregs is important, yet the transcriptional programs that control intratumoral Treg gene expression, and that are distinct from Tregs in healthy tissues, remain largely unknown. We profiled single-cell transcriptomes of CD4+ T cells in tumors and peripheral blood from patients with head and neck squamous cell carcinomas (HNSCC), in non-tumor tonsil tissues and in peripheral blood from healthy donors. We identified a subpopulation of activated Tregs expressing multiple tumor necrosis factor receptor (TNFR) genes (TNFR+ Tregs) that is highly enriched in the tumor microenvironment (TME) compared with non-tumor tissue and the periphery. TNFR+ Tregs are associated with worse prognosis in HNSCC and across multiple solid tumor types. Mechanistically, the transcription factor BATF is a central component of a gene regulatory network that governs key aspects of TNFR+ Tregs. CRISPR/Cas9-mediated BATF knockout in human activated Tregs in conjunction with bulk RNA sequencing, immunophenotyping and in vitro functional assays, corroborated the central role of BATF in limiting excessive activation and promoting the survival of human activated Tregs. Finally, we identified a suite of surface molecules reflective of the BATF-driven transcriptional network on intratumoral Tregs in patients with HNSCC. These findings uncover a primary transcriptional regulator of highly suppressive intratumoral Tregs, highlighting potential opportunities for therapeutic intervention in cancer without impacting immune homeostasis.
2023-08-03 | GSE239750 | GEO
Project description:Purpose: The purpose of this study is to identify the genome-wide binding sites for IRF4 interaction partners PU.1, BATF, and JunB in dendritic cells. These ChIP-seq data were integrated with gene expression analysis in IRF4-sufficient and -deficient BMDCs in order to assemble an IRF4 gene regulatory network. Hematopoietic bone marrow progenitors from C57BL/6 mice were differentiated with GM-CSF and IL-4 for 5 days. On day 6, BMDCs were stimulated for 6 hours with 100ng/ml LPS. Fixed chromatin was immunoprecipitated with anti-PU.1, BATF, and JunB antibodies and subjected to high-throughput sequencing. The sequencing data for the input DNA was previously submitted as GSM999807.
2013-12-22 | E-GEOD-52772 | biostudies-arrayexpress
Project description:Purpose: The purpose of this study is to identify the genome-wide binding sites for IRF4 interaction partners PU.1, BATF, and JunB in dendritic cells. These ChIP-seq data were integrated with gene expression analysis in IRF4-sufficient and -deficient BMDCs in order to assemble an IRF4 gene regulatory network.
2013-12-22 | GSE52772 | GEO
Project description:Purpose: Identification of the differentially expressed genes and metabolic pathways in resting and activated WT and BATF-deficient Treg cells Methods: RNA was purified from resting of stimulated (aCD3-CD38/IL-2 for 48 h)Treg cells isolated from WT or Foxp3CreBatffl/fl mice Results: Loss of BATF promotes triacylglycerol biosynthesis in Treg cells. Conclusions: BATF is crucial to coordinate the suppressive function and triacylglycerol metabolism of Treg cells.
2021-03-02 | GSE149197 | GEO
Project description:compare wild type and Batf-/- B cells activated for 0 1 or 2 days in vitro. WT or Batf deficient B cells were activated in vitro with LPS for 1 or 2 days, or left untreated. B cells were purified by MACS and activated, harvested and prepped for affymetrix gene expression profiling.
2011-05-15 | E-GEOD-28736 | biostudies-arrayexpress
Project description:In order to identify putative downstream targets of Batf in M1 cells, a microarray analysis was performed. Briefly, M1/Neg-RNAi (expressing control siRNA with no mammalian target) and M1/Batf-RNAi cells (expressing Batf targeting siRNA) were seeded in M1 growth medium at a density of 3 X 105/ml in 100mm culture dishes. Six plates were plated for each cell type. Within each group, three were labeled as + LIF and treated with leukemia inhibitory factor (LIF) (5 ng/ml) for 6 hours the following day. After 6 hours, the cells were harvested from all plates individually and RNA prepared. 5 µg of total RNA from the three individual samples representing each subgroup (M1/Neg-RNAi + LIF, - LIF; M1/Batf-RNAi + LIF, - LIF) were combined into one pool of RNA. EJT001 represents sample "M1/Neg-RNAi, no LIF)"; EJT002 represents sample "M1/Neg-RNAi, with LIF)"; EJT003 represents sample "M1/Batf-RNAi, no LIF)"; EJT004 represents sample "M1/Batf-RNAi, with LIF)". The four pools of RNA were shipped to Genome Explorations, Inc. for analysis using Affymetrix GeneChip technology. The differentially regulated genes were identified both within each group (+ LIF compared to - LIF) and between 2 goups (M1/Neg-RNAi and M1/Batf-RNAi).
2011-03-01 | E-MEXP-2995 | biostudies-arrayexpress
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.
2021-12-22 | GSE192387 | GEO
Project description:Group 3 innate lymphoid cells (ILC3s) are crucial for the maintenance of host-microbiota homeostasis in gastrointestinal mucosal tissues. The mechanisms that maintain lineage identity of intestinal ILC3s, and ILC3s-mediated orchestration of microbiota and mucosal T cell immunity are elusive. Here, we identified BATF as a gatekeeper of ILC3s homeostasis in the gut. Depletion of BATF in ILC3s resulted in excessive interferon-γ production, dysbiosis, aberrant T cell immune responses and spontaneous inflammatory bowel disease (IBD), which was considerably ameliorated by removal of adaptive immunity or antibiotic treatment. Mechanistically, BATF directly regulates ILC3s identity by globally shapes chromatin landscape of ILC3s. BATF directly binds to the cis-regulatory elements of type 1 effector genes, restrains their chromatin accessibility and inhibits their expression. Conversely, BATF promotes chromatin accessibility of genes involved in MHCII antigen processing and presentation pathways. Collectively, our findings reveal BATF is a promising candidate to maintain ILC3s stability and coordinate ILC3s–mediated control of intestinal homeostasis.
2022-08-31 | GSE168076 | GEO
Project description:compare wild type and Batf-/- B cells activated for 0 1 or 2 days in vitro. WT or Batf deficient B cells were activated in vitro with LPS for 1 or 2 days, or left untreated.
2011-05-15 | GSE28736 | GEO
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.
2021-12-22 | GSE192389 | GEO