Similar Datasets
Project description:The role of Krüppel-associated box zinc finger proteins (KZFPs), the largest family of repressive transcription factors (TFs) of the human genome, in the pathogenesis of diffuse large B cell lymphoma has not been addressed so far. By correlating the expression of KZFPs with patient outcome, we delineated a subset of 18 co-expressed KZFPs associated to poor prognosis, higher copy number alterations (CNA), and the suppression of hallmarks gene sets linked to immune rejection. Among them, the depletion of the ZNF587-ZNF417 pair of TF paralogs drastically impaired the proliferation of both activated B cell (ABC) and germinal center B (GCB) DLBCL cell lines, by triggering replicative stress through the awakening of dormant replication origins and profound alterations of the heterochromatin landscape. ZNF587/417 knockdown profoundly altered the transcriptomic landscape of U2932 (ABC) and OCI-Ly7 (GCB) cells, rewiring gene expression networks associated with good prognosis and upregulating interferon (IFN)/inflammatory-related genes through activation of the cGAS-STING DNA sensing pathway. These cells showed signs of altered immunogenicity with an enhanced MHC class I surface expression and a reshuffling of their immunopeptidome. Our study provides evidence that the ZNF587-ZNF417 paralog pair may promote lymphoma growth, the acquisition of genetic diversity, and its immune evasion by preventing excessive replicative stress. This suggests that these TFs participate in the epigenetic memory of lymphoma cells, thus highlighting the critical role of constitutive heterochromatin in maintaining the identity of poor-prognosis DLBCL.
2024-03-15 | PXD040500 | Pride
Project description:Heterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress leads to mitotic catastrophe and inflammatory responses promoting immune rejection. KRAB-containing zinc finger proteins (KZFPs) contribute to heterochromatin maintenance at transposable elements (TEs). Here, we describe how upregulation of a cluster of primate-specific KZFPs is associated with poor prognosis, increased copy number alterations, and suppression of immune responses in diffuse large B cell lymphoma (DLBCL). Depleting two of these KZFPs targeting evolutionarily recent TEs, ZNF587 and ZNF417, impairs proliferation of cells derived from DLBCL and several other tumor types. This correlates with heterochromatin redistribution, replicative stress, and cGAS-STING-mediated induction of an interferon/inflammatory response leading to enhanced susceptibility to macrophage-mediated phagocytosis, increased surface expression of HLA-I and presentation of a neo-immunopeptidome. Thus, cancer cells can subvert KZFPs to dampen TE-originating surveillance mechanisms, which likely facilitates clonal expansion, diversification, and immune evasion.
2024-01-18 | GSE229467 | GEO
Project description:Heterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress leads to mitotic catastrophe and inflammatory responses promoting immune rejection. KRAB-containing zinc finger proteins (KZFPs) contribute to heterochromatin maintenance at transposable elements (TEs). Here, we describe how upregulation of a cluster of primate-specific KZFPs is associated with poor prognosis, increased copy number alterations, and suppression of immune responses in diffuse large B cell lymphoma (DLBCL). Depleting two of these KZFPs targeting evolutionarily recent TEs, ZNF587 and ZNF417, impairs proliferation of cells derived from DLBCL and several other tumor types. This correlates with heterochromatin redistribution, replicative stress, and cGAS-STING-mediated induction of an interferon/inflammatory response leading to enhanced susceptibility to macrophage-mediated phagocytosis, increased surface expression of HLA-I and presentation of a neo-immunopeptidome. Thus, cancer cells can subvert KZFPs to dampen TE-originating surveillance mechanisms, which likely facilitates clonal expansion, diversification, and immune evasion.
2024-01-18 | GSE229469 | GEO
Project description:Heterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress leads to mitotic catastrophe and inflammatory responses promoting immune rejection. KRAB-containing zinc finger proteins (KZFPs) contribute to heterochromatin maintenance at transposable elements (TEs). Here, we describe how upregulation of a cluster of primate-specific KZFPs is associated with poor prognosis, increased copy number alterations, and suppression of immune responses in diffuse large B cell lymphoma (DLBCL). Depleting two of these KZFPs targeting evolutionarily recent TEs, ZNF587 and ZNF417, impairs proliferation of cells derived from DLBCL and several other tumor types. This correlates with heterochromatin redistribution, replicative stress, and cGAS-STING-mediated induction of an interferon/inflammatory response leading to enhanced susceptibility to macrophage-mediated phagocytosis, increased surface expression of HLA-I and presentation of a neo-immunopeptidome. Thus, cancer cells can subvert KZFPs to dampen TE-originating surveillance mechanisms, which likely facilitates clonal expansion, diversification, and immune evasion.
2024-01-18 | GSE229468 | GEO
Project description:Heterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress leads to mitotic catastrophe and inflammatory responses promoting immune rejection. KRAB-containing zinc finger proteins (KZFPs) contribute to heterochromatin maintenance at transposable elements (TEs). Here, we describe how upregulation of a cluster of primate-specific KZFPs is associated with poor prognosis, increased copy number alterations, and suppression of immune responses in diffuse large B cell lymphoma (DLBCL). Depleting two of these KZFPs targeting evolutionarily recent TEs, ZNF587 and ZNF417, impairs proliferation of cells derived from DLBCL and several other tumor types. This correlates with heterochromatin redistribution, replicative stress, and cGAS-STING-mediated induction of an interferon/inflammatory response leading to enhanced susceptibility to macrophage-mediated phagocytosis, increased surface expression of HLA-I and presentation of a neo-immunopeptidome. Thus, cancer cells can subvert KZFPs to dampen TE-originating surveillance mechanisms, which likely facilitates clonal expansion, diversification, and immune evasion.
2024-01-18 | GSE229465 | GEO
Project description:Heterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress leads to mitotic catastrophe and inflammatory responses promoting immune rejection. KRAB-containing zinc finger proteins (KZFPs) contribute to heterochromatin maintenance at transposable elements (TEs). Here, we describe how upregulation of a cluster of primate-specific KZFPs is associated with poor prognosis, increased copy number alterations, and suppression of immune responses in diffuse large B cell lymphoma (DLBCL). Depleting two of these KZFPs targeting evolutionarily recent TEs, ZNF587 and ZNF417, impairs proliferation of cells derived from DLBCL and several other tumor types. This correlates with heterochromatin redistribution, replicative stress, and cGAS-STING-mediated induction of an interferon/inflammatory response leading to enhanced susceptibility to macrophage-mediated phagocytosis, increased surface expression of HLA-I and presentation of a neo-immunopeptidome. Thus, cancer cells can subvert KZFPs to dampen TE-originating surveillance mechanisms, which likely facilitates clonal expansion, diversification, and immune evasion.
2024-01-18 | GSE229470 | GEO
Project description:Multiple nuclear localization domains have been identified in nuclear proteins, and they finely control nuclear import and functions of those proteins. ZNF268 is a typical KRAB-containing zinc finger protein (KRAB-ZFP), and previous studies have shown that the KRAB domain reinforces nuclear localization of KRAB-ZFPs by interacting with KAP1. In this study, we find that some of 24 zinc fingers of ZNF268 also possess nuclear localization activity. Results of mutagenesis studies suggest that KRAB and zinc fingers are both necessary, and they function both independently and cooperatively for the nuclear localization of ZNF268. However, the subnuclear targeting activities of KRAB and zinc fingers are different. KRAB targets proteins in nucleoplasm, but not in the nucleolus, which is mediated by interaction with KAP1, while zinc fingers target proteins in the whole nucleus uniformly. The cooperative activities of KAP1-KRAB-zinc fingers result in the precise nucleoplasmic, but not nucleolar localization of KRAB-ZFPs. Our studies reveal a novel mechanism for the subcellular localization of KRAB-ZFPs and may help us to further explore their biological functions.
| S-EPMC3960175 | biostudies-literature
Project description:Expression of Melanoma AntiGen Encoding (MAGE) genes, particularly MAGE-A3, has been correlated with aggressive clinical course, the acquisition of resistance to chemotherapy and poor clinical outcomes of melanoma and other malignancies. MAGE proteins bind to KAP1, a gene repressor and ubiquitin E3 ligase which also binds KRAB domain containing zinc finger transcription factors (KZNFs), and MAGE expression may affect KZNF mediated gene regulation. To investigate mechanisms for these effects, we tested the hypothesis that differences in KRAB domain composition affect KZNF poly-ubiquitination and determine whether MAGE expression increases, decreases, or has no effect on KZNFs mediated gene repression. Using an integrated reporter gene responsive to repression by KRAB domain fusion proteins, we found that MAGE-A3 relieved KZNF mediated repression and induced KZNF poly-ubiquitination and degradation in association with expression of the A+B box KRAB domain. In contrast, MAGE-A3 enhanced KAP1 mediated repression of KZNFs expressing A or A+b box KRAB domains but caused no increase in poly-ubiquitination or degradation. MAGE-A3 has no significant impact on KZNFs with KRAB domains containing the Scan box motif. These data support our hypothesis by showing that the effects of MAGE-A3 on gene repression depend on the type of KZNF KRAB domain involved.
| S-EPMC4221552 | biostudies-literature
Project description:Radio-chemotherapy with 5-flu orouracil (5-FU) is the standard of care treatment for patients with colorectal cancer, but it is only effective for a third of them. Despite our understanding of the mechanism of action of 5-FU, drug resistance remains a significant limitation to the clinical use of 5-FU, as both intrinsic and acquired chemoresistance represents the major obstacles for the success of 5-FU-based chemotherapy. In order to identify the mechanism of acquired resistance, 5-FU chemoresistance was induced in CRC cell lines by passaging cells with increasing concentrations of 5-FU. To study global molecular changes, quantitative proteomics and transcriptomics analyses were performed on these cell lines, comparing the resistant cells as well as the effect of chemo and radiotherapy. Interestingly, a very high proportion of downregulated genes were annotated as transcription factors coding for Krüppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs), the largest family of transcriptional repressors. Among nearly 350 KRAB-ZFPs, almost a quarter were downregulated after the induction of a 5-FU-resistance including a common one between the three CRC cell lines, ZNF649, whose role is still unknown. To confirm the observations of the proteomic and transcriptomic approaches, the abundance of 20 different KZFPs and control mRNAs was validated by RT-qPCR. In fact, several KZFPs were no longer detectable using qPCR in cell lines resistant to 5-FU, and the KZFPs that were downregulated only in one or two cell lines showed similar pattern of expression as measured by the omics approaches. This proteomic, transcriptomic and genomic analysis of intrinsic and acquired resistance highlights a possible new mechanism involved in the cellular adaptation to 5-FU and therefore identifies potential new therapeutic targets to overcome this resistance.
| S-EPMC8981854 | biostudies-literature
Project description:Krüppel-associated box (KRAB) zinc finger proteins (KZNFs) recognize and repress transposable elements (TEs); TEs are DNA elements that are capable of replicating themselves throughout our genomes with potentially harmful consequences. However, genes from this family of transcription factors have a much wider potential for genomic regulation. KZNFs have become integrated into gene-regulatory networks through the control of TEs that function as enhancers and gene promoters; some KZNFs also bind directly to gene promoters, suggesting an additional, more direct layer of KZNF co-option into gene-regulatory networks. Binding site analysis of ZNF519, ZNF441, and ZNF468 suggests the structural evolution of KZNFs to recognize TEs can result in coincidental binding to gene promoters independent of TE sequences. We show a higher rate of sequence turnover in gene promoter KZNF binding sites than neighboring regions, implying a selective pressure is being applied by the binding of a KZNF. Through CRISPR/Cas9 mediated genetic deletion of ZNF519, ZNF441, and ZNF468, we provide further evidence for genome-wide co-option of the KZNF-mediated gene-regulatory functions; KZNF knockout leads to changes in expression of KZNF-bound genes in neuronal lineages. Finally, we show that the opposite can be established upon KZNF overexpression, further strengthening the support for the role of KZNFs as bona-fide gene regulators. With no eminent role for ZNF519 in controlling its TE target, our study may provide a snapshot into the early stages of the completed co-option of a KZNF, showing the lasting, multilayered impact that retrovirus invasions and host response mechanisms can have upon the evolution of our genomes.
| S-EPMC10653712 | biostudies-literature