Similar Datasets
Project description:Gene expression aberration is a hallmark of cancers, but the mechanisms underlying such aberrations remain unclear. Human endogenous retroviruses (HERVs) are genomic repetitive elements that potentially function as enhancers. Since numerous HERVs are epigenetically activated in tumors, their activation could cause global gene expression aberrations in tumors. Here, we show that HERV activation in tumors leads to the up-regulation of hundreds of transcriptional suppressors, namely, Krüppel-associated box domain-containing zinc-finger family proteins (KZFPs). KZFP genes are preferentially encoded nearby the activated HERVs in tumors and transcriptionally regulated by these adjacent HERVs. Increased HERV and KZFP expression in tumors was associated with better disease conditions. Increased KZFP expression in cancer cells altered the expression of genes related to the cell cycle and cell-matrix adhesion and suppressed cellular growth, migration, and invasion abilities. Our data suggest that HERV activation in tumors drives the synchronized elevation of KZFP expression, presumably leading to tumor suppression.
| S-EPMC7577720 | biostudies-literature
Project description:Roles of human endogenous retroviruses and KRAB-zinc finger proteins in tumor progression
| PRJNA594759 | ENA
Project description:Retroviruses have been invading mammalian germlines for millions of years, accumulating in the form of endogenous retroviruses (ERVs) that account for nearly one-tenth of the mouse and human genomes. ERVs are epigenetically silenced during development, yet the cellular factors recognizing ERVs in a sequence-specific manner remain elusive. Here we demonstrate that ZFP809, a member of the Krüppel-associated box zinc finger protein (KRAB-ZFP) family, initiates the silencing of ERVs in a sequence-specific manner via recruitment of heterochromatin-inducing complexes. ZFP809 knockout mice display highly elevated levels of ZFP809-targeted ERVs in somatic tissues. ERV reactivation is accompanied by an epigenetic shift from repressive to active histone modifications but only slight destabilization of DNA methylation. Importantly, using conditional alleles and rescue experiments, we demonstrate that ZFP809 is required to initiate ERV silencing during embryonic development but becomes largely dispensable in somatic tissues. Finally, we show that the DNA-binding specificity of ZFP809 is evolutionarily conserved in the Muroidea superfamily of rodents and predates the endogenization of retroviruses presently targeted by ZFP809 in Mus musculus. In sum, these data provide compelling evidence that ZFP809 evolved to recognize foreign DNA and establish histone modification-based epigenetic silencing of ERVs.
| S-EPMC4358406 | biostudies-literature
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:Krüppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) are one of the largest groups of transcription factors encoded by tetrapods, with 378 members in human alone. KZFP genes are often grouped in clusters reflecting amplification by gene and segment duplication since the gene family first emerged more than 400 million years ago. Previous work has revealed that many KZFPs recognize transposable element (TE)-embedded sequences as genomic targets, and that KZFPs facilitate the co-option of the regulatory potential of TEs for the benefit of the host. Here, we present a comprehensive survey of the genetic features and genomic targets of human KZFPs, notably completing past analyses by adding data on close to a hundred family members. General principles emerge from our study of the TE-KZFP regulatory system, which point to multipronged evolutionary mechanisms underlaid by highly complex and combinatorial modes of action with strong influences on human speciation.
| S-EPMC10547255 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-01-24 | GSE144192 | GEO
Project description:Transcriptional silencing of endogenous retroviruses (ERV) defends against active retrotransposition and disease, including overproduction of non-ecotropic ERV (NEERV) envelope and resultant nephritis observed in lupus-prone mice. However, a repressor targeting NEERV loci has not yet been identified. In this study, we identified suppressor of NEERV (Snerv), a Krüppel-associated box zinc finger protein gene responsible for NEERV repression in multiple inbred mouse strains. We show that SNERV binds to the NEERV long terminal repeat and recruits the transcriptional regulator KAP1. Germline deletion of Snerv leads to increased activating chromatin modifications, transcription, and expression of envelope glycoprotein, gp70, from NEERV loci. We found that the NZB and 129 genomes, which overexpress NEERV gp70, cannot rescue defective NEERV repression in F1 crosses to Snerv-/- mice, thus mapping the long sought-after Sgp3 and Gv1 loci to Snerv and demonstrating that loss of SNERV is responsible for the overexpression of the lupus autoantigen gp70. We also found elevated expression of human ERV transcripts in lupus patients compared to healthy controls, and identify putative KRAB-ZFP genes whose expression inversely correlates with human ERV levels. Collectively, our study highlights a role for the KRAB-ZFP, Snerv, in mouse NEERV repression, and suggests similar ERV dysregulation in human lupus disease.
2019-12-31 | GSE121640 | GEO
Project description:BackgroundTransposable element-embedded regulatory sequences (TEeRS) and their KRAB-containing zinc finger protein (KZFP) controllers are increasingly recognized as modulators of gene expression. We aim to characterize the contribution of this system to gene regulation in early human development and germ cells.ResultsHere, after studying genes driven by the long terminal repeat (LTR) of endogenous retroviruses, we identify the ape-restricted ZNF676 as the sequence-specific repressor of a subset of contemporary LTR12 integrants responsible for a large fraction of transpochimeric gene transcripts (TcGTs) generated during human early embryogenesis. We go on to reveal that the binding of this KZFP correlates with the epigenetic marking of these TEeRS in the germline, and is crucial to the control of genes involved in ciliogenesis/flagellogenesis, a biological process that dates back to the last common ancestor of eukaryotes.ConclusionThese results illustrate how KZFPs and their TE targets contribute to the evolutionary turnover of transcription networks and participate in the transgenerational inheritance of epigenetic traits.
| S-EPMC8767690 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-01-18 | GSE229471 | GEO
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