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Loss of ZNF408 Is Linked to Immune Escape in Breast Carcinogenesis [RNA-seq]

ABSTRACT: Understanding cancer immune escape is important to the comprehension of cancer development and to the development of cancer immunotherapy. We report here that ZNF408, encoded by a gene linked to familial exudative vitreoretinopathy (FEVR) and autosomal recessive retinitis pigmentosa (RP), is physically associated with the chromatin remodeler SETD1A/COMPASS complex in breast cancer cells. The ZNF408/SETD1A/COMPASS complex orchestrates the transcriptional activation of a cohort of genes via histone H3K4 trimethylation, particularly STING1 that are critically involved in innate immune response, leading to the release of multiple cytokines and activation of cytotoxic lymphocyte cells in tumor microenvironment. ZNF408 enhances STING expression and promotes anti-tumor immune responses both in vitro and in vivo. Importantly, the expression of ZNF408 is downregulated in breast carcinomas, and its level of expression is positively correlated with that of STING1 and negatively correlated with the histological grade of breast cancer. High ZNF408 is also correlated with high CD8+ T cell infiltration and favorable prognosis of breast cancer patients. Our study uncovers an important role for ZNF408 in innate immune response, supporting further investigations of the ZNF408-SETD1A/COMPASS-STING1 axis in cancer immune escape as well as in other ZNF408-associated diseases including FEVR and RP.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254413 | GEO | 2024/06/26

REPOSITORIES: GEO

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Loss of ZNF408 Is Linked to Immune Escape in Breast Carcinogenesis [CUT&Tag]

Project description:Understanding cancer immune escape is important to the comprehension of cancer development and to the development of cancer immunotherapy. We report here that ZNF408, encoded by a gene linked to familial exudative vitreoretinopathy (FEVR) and autosomal recessive retinitis pigmentosa (RP), is physically associated with the chromatin remodeler SETD1A/COMPASS complex in breast cancer cells. The ZNF408/SETD1A/COMPASS complex orchestrates the transcriptional activation of a cohort of genes via histone H3K4 trimethylation, particularly STING1 that are critically involved in innate immune response, leading to the release of multiple cytokines and activation of cytotoxic lymphocyte cells in tumor microenvironment. ZNF408 enhances STING expression and promotes anti-tumor immune responses both in vitro and in vivo. Importantly, the expression of ZNF408 is downregulated in breast carcinomas, and its level of expression is positively correlated with that of STING1 and negatively correlated with the histological grade of breast cancer. High ZNF408 is also correlated with high CD8+ T cell infiltration and favorable prognosis of breast cancer patients. Our study uncovers an important role for ZNF408 in innate immune response, supporting further investigations of the ZNF408-SETD1A/COMPASS-STING1 axis in cancer immune escape as well as in other ZNF408-associated diseases including FEVR and RP.

2024-06-26 | GSE254412 | GEO

Loss of ZNF408 Is Linked to Immune Escape in Breast Carcinogenesis [ATAC-seq]

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SETD1A protects from senescence through regulation of the mitotic gene expression program

Project description:SETD1A, a member of the Set1/COMPASS family maintaining H3K4 methylation in the promoters of transcriptionally active genes, is critical for the execution of developmental gene expression and is overexpressed in multiple cancers including breast cancer1-3. Here we show that SETD1A is essential for supporting cellular mitotic processes and consequentially, its depletion leads to senescence. SETD1A directly regulates the expression of several genes orchestrating mitosis and DNA damage responses and its depletion results in multiple mitotic defects including chromosome misalignment and segregation defects. Senescence-associated cell cycle arrest in SETD1A knockdown cells is independent of the mutational status of p53, RB and p16, key mediators of this process, instead, is sustained through direct transcriptional suppression of SKP2, the ubiquitin ligase, which degrades p27 and p21. Rare cells escape senescence and re-enter the cell cycle by restoring SKP2 expression but with enhanced genomic instability. In >200 cancer cell lines and in primary circulating tumor cells, expression of SETD1A correlates with genes involved in mitosis and cell cycle suggesting a role in suppressing senescence induced by aberrant mitosis. Thus, SETD1A encodes a chromatin modifier, whose modulation may maintain the balance between senescence and genomic instability in cells.

2019-07-08 | GSE117427 | GEO

Epigenetic modification of GR enhancers by SETD1A/COMPASS complex in murine macrophages

Project description:Nuclear interaction studies by ChIP coupled with mass spectrometry identified the COMPASS/SETD1A complex as interaction partner of the glucocorticoid receptor (GR) in murine bone marrow-derived macrophages (BMDMs). Here, we profiled the occupancy of SETD1A and CXXC1, two subunits of the COMPASS/SETD1A complex in murine macrophages after LPS and Dex+LPS stimulation. We show, that GR recuits SETD1A and CXXC1 to GR enhancer and that SETD1A recruitment does correlate with changes in H3K4methylation at some of those enhancers.

2020-12-31 | GSE136070 | GEO

H3K4methylation in Setd1a loss-of-function Raw264.7 cells upon LPS or Dex+LPS stimulation

Project description:Nuclear interaction studies by ChIP coupled with mass spectrometry identified the COMPASS/SETD1A complex as interaction partner of the glucocorticoid receptor (GR) in murine bone marrow-derived macrophages (BMDMs). Here, we profiled H3K4me1, H3K4me2 and H3K4me3 in wild-type and Setd1a hypermorphic (Setd1aDel/+) Raw264.7 cells after LPS and Dex+LPS stimulation by spike-in ChIP-Seq.

2020-12-31 | GSE138017 | GEO

BOD1L mediates chromatin binding and non-canonical function of H3K4 methyltransferase SETD1A (RNA-seq)

Project description:The H3K4 methyltransferase SETD1A plays an essential role in both development and cancer. However, essential components involved in SETD1A chromatin binding remain unclear. Here, we discovered that BOD1L exhibits the highest correlated co-dependency with SETD1A in human cancer cell lines. BOD1L knockout reduces leukemia cells in vitro and in vivo, and mimics the transcriptional profiles observed in SETD1A knockout cells. The loss of BOD1L immediately reduced SETD1A distribution at transcriptional start sites (TSS) and induces transcriptional elongation defect along with the increasing of RNA polymerase II at TSS, but did not cause the reduction of H3K4me3. The Shg1 domain of BOD1L has a DNA binding ability, and recruit SETD1A to chromatin through the association with SETD1A FLOS domain. In addition, the BOD1L-SETD1A complex associates with transcriptional regulators, including E2Fs. These results reveal that BOD1L mediates chromatin and SETD1A, and regulates the non-canonical function of SETD1A in transcription.

2024-06-25 | GSE258789 | GEO

BOD1L mediates chromatin binding and non-canonical function of H3K4 methyltransferase SETD1A (ChIP-seq)

2024-06-25 | GSE258788 | GEO

ASH2L, a COMPASS core subunit, is involved in the cell invasion and migration of triple-negative breast cancer cells through the epigenetic control of histone H3 lysine 4 methylation.

Project description:ASH2L (Absent-Small-Homeotic-2-Like protein) is a core subunit of the COMPASS (COMplex of Proteins ASsociated with Set1) complexes, the most notable writer of the methylation of histone H3 lysine 4 (H3K4). The COMPASS complex regulates active promoters or enhancers, and its dysfunction is associated with aberrant development and disease. Here, we demonstrated that ASH2L mediated the cell invasion and migration activity of triple-negative breast cancer cells through the interaction with the COMPASS components and the target genomic regions. Transcriptome analysis indicated a potential correlation between ASH2L and the genes involved in inflammatory/immune responses. Among them, we found that the intrinsic expression of IL1B (interleukin 1 beta), an essential proinflammatory gene, was directly regulated by ASH2L. These results revealed a novel role of ASH2L on the maintenance of breast cancer malignancy possibly through H3K4 methylation of the target inflammatory/immune responsive genes.

2023-06-09 | GSE228517 | GEO

SETD1A protects from senescence through regulation of the mitotic gene expression program

Project description:SETD1A, a Set1/COMPASS family member maintaining histone-H3-lysine-4 (H3K4) methylation on transcriptionally active promoters, is overexpressed in breast cancer. Here we show that SETD1Asupports mitotic processes and consequentially, its knockdown induces senescence, independent of mutations in p53, RBand p16, known senescence mediators. The following labeling scheme was used: bridge_1; TMT1_126 A549_GFPctrl_Day3_Repl1; TMT1_127n A549_shSETD1A#1_Day3_Repl1; TMT1_127c A549_shSETD1A#2_Day3_Repl1; TMT1_128n A549_GFPctrl_Day5_Repl1; TMT1_128c A549_shSETD1A#1_Day5_Repl1; TMT1_129n A549_shSETD1A#2_Day5_Repl1; TMT1_129c M231_GFPctrl_Day3; TMT1_130n M231_GFP_ctrl_Day5; TMT1_130c bridge_2; TMT1_131 bridge_1; TMT2_126 A549_GFP_ctrl_Day3_Repl2; TMT2_127n A549_shSETD1A#1_Day3_Repl2; TMT2_127c A549_shSETD1A#2_Day3_Repl2; TMT2_128n A549_GFPctrl_Day5_Repl2; TMT2_128c A549_shSETD1A#1_Day5_Repl2; TMT2_129n A549_shSETD1A#2_Day5_Repl2; TMT2_129c M231_shSETD1A#2_Day3; TMT2_130n M231_shSETD1A#2_Day5; TMT2_130c bridge_2; TMT2_131

2019-05-09 | MSV000083763 | MassIVE

An H3K4me3 reader, BAP18 as an adaptor of COMPASS-like core subunits co-activates ERa action to confer to tamoxifen resistance in breast cancer

Project description:Estrogen receptor alpha (ERalpha signaling pathway is essential for ERalpha positive breast cancer progression and endocrine therapy resistance. BPTF associated protein of 18kDa (BAP18) has been recognized as a crucial H3K4me3 reader. However, the whole genomic occupation of BAP18 and its biological function in breast cancer are still elusive. Here, we found that higher expression of BAP18 in ERalpha positive breast cancer is positively correlated with poor prognosis. ChIP-seq analysis further demonstrated that the half estrogen response elements (EREs) and the CCCTC binding factor (CTCF) binding sites are the significant enrichment sites found in estrogen-induced BAP18 binding sites. In addition, we provide the evidence to demonstrate that BAP18 as a novel co-activator of ERalpha is required for the recruitment of COMPASS-like core subunits to cis-regulatory element of ERalpha target genes in breast cancer cells. BAP18 is recruited to the promoter regions of estrogen-induced genes, accompanied with the enrichment of the lysine 4-trimethylated histone H3 tail (H3K4me3) in the presence of E2. Furthermore, BAP18 promotes cell growth and confers to ERalpha antagonist tamoxifen resistancein ERalpha positive breast cancer. Our data suggest that BAP18 facilitates the association between ERalpha and COMPASS-like core subunits, which might be an essential epigenetic therapeutic target for breast cancer.

2020-11-09 | GSE144641 | GEO

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