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Endogenous retroviruses drive KRAB zinc-finger protein family expression for tumor suppression.

ABSTRACT: 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.

SUBMITTER: Ito J

PROVIDER: S-EPMC7577720 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Roles of human endogenous retroviruses and KRAB-zinc finger proteins in tumor progression

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-09-29 | GSE141803 | GEO

The KRAB zinc finger protein ZFP809 is required to initiate epigenetic silencing of endogenous retroviruses.

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

The KRAB zinc finger protein SNERV represses proviral endogenous retroviruses and underlies the Sgp3 and Gv1 loci

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

Roles of human endogenous retroviruses and KRAB-zinc finger proteins in tumor progression

Project description:Roles of human endogenous retroviruses and KRAB-zinc finger proteins in tumor progression

| PRJNA594759 | ENA

KRAB zinc finger protein ZNF676 controls the transcriptional influence of LTR12-related endogenous retrovirus sequences.

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

Zinc fingers function cooperatively with KRAB domain for nuclear localization of KRAB-containing zinc finger proteins.

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

KRAB-independent suppression of neoplastic cell growth by the novel zinc finger transcription factor KS1.

Project description:The study of zinc finger proteins has revealed their potential to act as oncogenes or tumor suppressors. Here we report the molecular, biochemical, and functional characterization of KS1 (KRAB/zinc finger suppressor protein 1), a novel, ubiquitously expressed zinc finger gene initially isolated from a rat pancreas library. KS1 contains 10 C2H2 zinc fingers, a KRAB-A/B motif, and an ID sequence that has been shown previously to participate in growth factor-regulated gene expression. Northern blot analysis using pancreatic cell lines demonstrates that KS1 mRNA is inducible by serum and epidermal growth factor, suggesting a role for this gene in cell growth regulation. Biochemical analysis reveals that KS1 is a nuclear protein containing two transcriptional repressor domains, R1 and R2. R1 corresponds to the KRAB-A motif, whereas R2 represents a novel sequence. Transformation assays using NIH3T3 cells demonstrate that KS1 suppresses transformation by the potent oncogenes Ha-ras, Galpha12, and Galpha13. Deletion of the R1/ KRAB-A domain does not modify the transformation suppressive activity of KS1, whereas deletion of R2 abolishes this function. Thus, KS1 is a novel growth factor-inducible zinc finger transcriptional repressor protein with the potential to protect against neoplastic transformation induced by several oncogenes.

| S-EPMC509142 | biostudies-other

Widespread correlation of KRAB zinc finger protein binding with brain-developmental gene expression patterns.

Project description:The large family of KRAB zinc finger (KZNF) genes are transcription factors implicated in recognizing and repressing repetitive sequences such as transposable elements (TEs) in our genome. Through successive waves of retrotransposition-mediated insertions, various classes of TEs have invaded mammalian genomes at multiple timepoints throughout evolution. Even though most of the TE classes in our genome lost the capability to retrotranspose millions of years ago, it remains elusive why the KZNFs that evolved to repress them are still retained in our genome. One hypothesis is that KZNFs become repurposed for other regulatory roles. Here, we find evidence that evolutionary changes in KZNFs provide them not only with the ability to repress TEs, but also to bind to gene promoters independent of TEs. Using KZNF binding site data in conjunction with gene expression values from the Allen Brain Atlas, we show that KZNFs have the ability to regulate gene expression in the human brain in a region-specific manner. Our analysis shows that the expression of KZNFs shows correlation with the expression of their target genes, suggesting that KZNFs have a direct influence on gene expression in the developing human brain. The extent of this regulation and the impact it has on primate brain evolution are still to be determined, but our results imply that KZNFs have become widely integrated into neuronal gene regulatory networks. Our analysis predicts that gene expression networks have been repeatedly innovated throughout primate evolution, continuously gaining new layers of gene regulation mediated by both TEs and KZNFs in our genome. This article is part of a discussion meeting issue 'Crossroads between transposons and gene regulation'.

| S-EPMC7061980 | biostudies-literature

KRAB zinc finger protein diversification drives mammalian interindividual methylation variability.

Project description:Most transposable elements (TEs) in the mouse genome are heavily modified by DNA methylation and repressive histone modifications. However, a subset of TEs exhibit variable methylation levels in genetically identical individuals, and this is associated with epigenetically conferred phenotypic differences, environmental adaptability, and transgenerational epigenetic inheritance. The evolutionary origins and molecular mechanisms underlying interindividual epigenetic variability remain unknown. Using a repertoire of murine variably methylated intracisternal A-particle (VM-IAP) epialleles as a model, we demonstrate that variable DNA methylation states at TEs are highly susceptible to genetic background effects. Taking a classical genetics approach coupled with genome-wide analysis, we harness these effects and identify a cluster of KRAB zinc finger protein (KZFP) genes that modifies VM-IAPs in trans in a sequence-specific manner. Deletion of the cluster results in decreased DNA methylation levels and altered histone modifications at the targeted VM-IAPs. In some cases, these effects are accompanied by dysregulation of neighboring genes. We find that VM-IAPs cluster together phylogenetically and that this is linked to differential KZFP binding, suggestive of an ongoing evolutionary arms race between TEs and this large family of epigenetic regulators. These findings indicate that KZFP divergence and concomitant evolution of DNA binding capabilities are mechanistically linked to methylation variability in mammals, with implications for phenotypic variation and putative paradigms of mammalian epigenetic inheritance.

| S-EPMC7733849 | biostudies-literature

Gv1, a Zinc Finger Gene Controlling Endogenous MLV Expression.

Project description:The genomes of inbred mice harbor around 50 endogenous murine leukemia virus (MLV) loci, although the specific complement varies greatly between strains. The Gv1 locus is known to control the transcription of endogenous MLVs and to be the dominant determinant of cell-surface presentation of MLV envelope, the GIX antigen. Here, we identify a single Krüppel-associated box zinc finger protein (ZFP) gene, Zfp998, as Gv1 and show it to be necessary and sufficient to determine the GIX+ phenotype. By long-read sequencing of bacterial artificial chromosome clones from 129 mice, the prototypic GIX+ strain, we reveal the source of sufficiency and deficiency as splice-acceptor variations and highlight the varying origins of the chromosomal region encompassing Gv1. Zfp998 becomes the second identified ZFP gene responsible for epigenetic suppression of endogenous MLVs in mice and further highlights the prominent role of this gene family in control of endogenous retroviruses.

| S-EPMC8136514 | biostudies-literature

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