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Satb1 Overexpression Drives Tumor-Promoting Activities In Cancer-Associated Dendritic Cells

ABSTRACT: Special AT-rich sequence-binding protein-1 (Satb1) governs genome-wide transcriptional programs. Using a new conditional knockout mouse, we found that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating MHC-II expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC-II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46+ inflammatory DCs that universally infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. Correspondingly, specific in vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but relentless Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE76776 | GEO | 2016/01/13

SECONDARY ACCESSION(S): PRJNA308573

REPOSITORIES: GEO

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Satb1 Overexpression Drives Tumor-Promoting Activities In Cancer-Associated Dendritic Cells

Project description:Special AT-rich sequence-binding protein-1 (Satb1) governs genome-wide transcriptional programs. Using a new conditional knockout mouse, we found that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating MHC-II expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC-II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46+ inflammatory DCs that universally infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. Correspondingly, specific in vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but relentless Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression. RNA-seq with whild type and knocked-down Satb1

2016-01-13 | E-GEOD-76776 | biostudies-arrayexpress

Zbtb46 coordinates tumor angiogenesis and tumor immunity to control tumor outcome

Project description:Tumor-angiogenesis and -immunity play critical roles in cancer progression and outcome. The existence of an inverse correlation hints at common regulatory mechanism(s) controlling these two processes. Here, we report that Zbtb46, a repressive transcription factor and widely accepted marker for classical dendritic cells (DCs), constitutes one such regulatory mechanism in the tumor microenvironment (TME) and is downregulated in both DCs and endothelial cells (ECs) by tumor-derived factors to facilitate robust tumor growth. This downregulation leads to the development of hallmark features of a pro-tumor environment, including dysfunctional vasculature and immunosuppressive cell accumulation. Analysis of cancer patient data revealed a similar association of a low ZBTB46 expression with an immunosuppressive TME and a worse prognosis. In contrast, upon enforced Zbtb46 expression, the hallmark TME features are mitigated, and tumor growth is restricted. Mechanistically, Zbtb46-deficient ECs were highly angiogenic, and Zbtb46-deficient bone-marrow precursors upregulated Cebpb and showed enhanced myeloid lineage output. Conversely, Zbtb46-maintenance normalizes ECs and, by suppressing Cebpb, skews the polarization of bone-marrow precursors towards more DCs and fewer macrophages, leading to an immune-hot TME. Remarkably, Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in pre-clinical models. These findings identify Zbtb46 as a common regulatory mechanism for angiogenesis and for non-hematopoietic-stem-cell-mediated myeloid lineage skewing in cancer and suggest that maintaining its expression could have therapeutic benefits.

2024-02-24 | GSE226087 | GEO

Single Cell RNA sequencing of the non-tumor components of the tumor mass after either empty vector control or Zbtb46 overexpressing lentiviral intratumoral treatments

Project description:Tumor-angiogenesis and -immunity play critical roles in cancer progression and outcome. An inverse correlation of these two1 hints at common regulatory mechanism(s). Here, we report that Zbtb46, a repressive transcription factor and a widely accepted marker for classical dendritic cells (DCs)2,3, constitutes one such regulatory mechanism. Zbtb46 was downregulated in both DCs and endothelial cells (ECs) by tumor-derived factors to facilitate robust tumor growth. Zbtb46 downregulation led to a hallmark pro-tumor microenvironment (TME), including dysfunctional vasculature and immunosuppressive cell accumulation. Analysis of cancer patient data revealed a similar association of low ZBTB46 expression with an immunosuppressive TME and a worse prognosis. In contrast, enforced Zbtb46 expression brought dynamic changes in the TME landscape to mitigate the pro-tumor features and to enhance anti-tumor immune components, restricting tumor growth. Mechanistically, Zbtb46-deficient ECs were highly angiogenic, and Zbtb46-deficient bone-marrow progenitors upregulated Cebpb and diverted the DC program to myeloid lineage output, potentially explaining the myeloid lineage skewing phenomenon in cancer4. Conversely, enforced Zbtb46 expression normalized tumor vessels and, by suppressing Cebpb, skewed bone-marrow precursors towards more DC generation over macrophages, leading to an immune-hot TME. Remarkably, Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in pre-clinical models. These findings identify Zbtb46 as a common regulatory mechanism for angiogenesis and for myeloid lineage skewing in cancer and suggest that maintaining its expression could have therapeutic benefits.

2024-07-05 | GSE264124 | GEO

Microarray expression data from WT and IRF4 KO Sirp-a+ DCs

Project description:Cross-presentation of cell-associated antigens is carried out by classical DCs (cDCs) and monocyte-derived DCs (Mo-DCs), but whether a similar or distinct program exists for this process is unknown. In examining this issue, we discovered that only Ly-6ChiTremL4– monocytes, but not Ly-6ChiTremL4+ monocytes, can differentiate into Zbtb46+ Mo-DCs in response to GM-CSF and IL-4. However, Ly-6ChiTremL4+ monocytes were committed to Nur77-dependent development of Ly-6CloTremL4+ monocytes. Further, differentiation of monocytes with GM-CSF required addition of IL-4 to generate Zbtb46+ Mo-DCs that cross-presented as efficiently as CD24+ cDCs, which was accompanied by increased Batf3 and Irf4 expression. Unlike cDCs, Mo-DCs required only IRF4, and not Batf3, for cross-presentation. Further, Irf4–/– monocytes failed to develop into Zbtb46+ Mo-DCs, and instead developed into macrophages. Thus, cDCs and Mo-DCs use distinct transcriptional programs for cross-presentation that may drive different antigen-processing pathways. These differences may influence development of therapeutic DC vaccines based on Mo-DCs.

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Microarray expression data from circulating blood monocytes

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Microarray expression data from monocytes, Mo-DCs and CD24 DCs

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SATB1 prevents immune cell infiltration by regulating chromatin organization and gene expression of a chemokine gene cluster in T cells [RNA-seq]

Project description:The precise regulation of T lymphocyte development and functions is crucial for preventing the initiation and progression of autoimmunity. SATB1, a key regulator of T cell development, governs lineage-specific transcriptional programs. However, its role in autoimmunity remains unclear. Here we show that conditional knockout of Satb1 in CD4+ T cells in mice led to T cell hyperactivation and inflammatory cell infiltration in the lungs and stomach. By performing transcriptome profiling, we show that the loss of SATB1 led to the aberrant upregulation of chemokines, particularly the ones belonging to the CC subfamily. Treating Satb1 conditional knockout mice with the inhibitor of the CC chemokine receptor alleviated inflammatory cell infiltration and autoimmune phenotypes. Intriguingly, SATB1's transcriptional regulation of chemokine genes could not be attributed to its direct binding to chemokine promoters or modulation of H3K27Ac. Instead, SATB1 exerted its regulatory effects through the control of higher-order chromatin organization at the CC chemokine locus. The loss of SATB1 led to the emergence of a new chromatin domain encompassing the Ccl3, Ccl4, Ccl5, Ccl6, and Ccl9 genes and a distal enhancer, resulting in increased contacts between the enhancer and all five chemokine genes, thus inducing their upregulation. Collectively, these results demonstrate that SATB1 safeguards organisms against autoimmunity by ensuring proper chemokine expression and preventing inflammatory cell infiltration, providing valuable insights into the understanding of autoimmune diseases.

2024-09-27 | GSE224976 | GEO

SATB1 prevents immune cell infiltration by regulating chromatin organization and gene expression of a chemokine gene cluster in T cells

2024-09-25 | GSE224977 | GEO

Expression data from Zbtb46- CDPs, Zbtb46+ CDPs, and pre-CD8 DCs

Project description:Expression data from Zbtb46- CDPs, Zbtb46+ CDPs, and pre-CD8 DCs

| PRJNA509678 | ENA

Microarray analysis of Zbtb46 KO CD4+ splenic DCs and bone marrow erythroid progenitors

Project description:Zbtb46 represses G-CSFR and LifR in cDCs Zbtb46 does not significantly affect gene expression in erythroid progenitors WT, Het, and KO cells were sorted from BM or spleen and analyzed. Pre MegE cells were sorted as CD117+ CD150+ CD105-CD41-CD16/32-. Pre CFU-E cells were sorted as CD117+ CD150+ CD105lo CD41- CD16/32-. CFU-E cells were sorted as CD117+ CD150- CD105+ Cd41- CD16/32-. Splenic CD4+ DCs were sorted as B220- CD11c+ MHCII+ CD8- CD172+ CD11b+ CD4+.

2012-05-20 | E-GEOD-37028 | biostudies-arrayexpress

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