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ZNF695 Represses Hepatic Genes and Regulates H3K9me3-Heterochromatin [CUT&RUN]

ABSTRACT: In any cell type, repetitive elements and alternative lineage genes can be silenced by heterochromatin marked by H3K9me3 and/or H3K27me3. During cellular reprogramming to pluripotency and to liver, genes marked by H3K9me3 are the most difficult to activate. Given that KRAB domain-containing, zinc finger proteins (KRAB-ZFPs) can direct repressive H3K9me3 at genes and transposable elements, we sought to identify KRAB-ZFPs that silence liver genes in non-liver lineages and could be useful for down-regulating during human fibroblast to hepatocyte (hiHep) reprogramming. We identified six KRAB-ZFPs that are essentially not expressed in liver or BJ fibroblasts, but are expressed in many other tissues. We knocked down each KRAB-ZFP during hepatic reprogramming of human fibroblasts and found that only knockdown of primate-specific ZNF695 allowed hundreds of hepatic genes in H3K9me3-heterochromatin to be derepressed. ZNF695 localizes primarily at LINE repeat elements and at gene introns that were linked to gene expression changes. ZNF695 exhibits nuclear mobility characteristics similar to well-characterized heterochromatin proteins. While most KRAB-ZFPs tested that exhibit diminution in one tissue (liver) did not functionally repress that tissue’s genes in another cell type, our strategy revealed a KRAB-ZFP that can be targeted to allow H3K9me3-heterochromatic genes to be derepressed during cellular reprogramming.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207017 | GEO | 2024/10/31

REPOSITORIES: GEO

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ZNF695 Represses Hepatic Genes and Regulates H3K9me3-Heterochromatin [RNA-seq]

Project description:In any cell type, repetitive elements and alternative lineage genes can be silenced by heterochromatin marked by H3K9me3 and/or H3K27me3. During cellular reprogramming to pluripotency and to liver, genes marked by H3K9me3 are the most difficult to activate. Given that KRAB domain-containing, zinc finger proteins (KRAB-ZFPs) can direct repressive H3K9me3 at genes and transposable elements, we sought to identify KRAB-ZFPs that silence liver genes in non-liver lineages and could be useful for down-regulating during human fibroblast to hepatocyte (hiHep) reprogramming. We identified six KRAB-ZFPs that are essentially not expressed in liver or BJ fibroblasts, but are expressed in many other tissues. We knocked down each KRAB-ZFP during hepatic reprogramming of human fibroblasts and found that only knockdown of primate-specific ZNF695 allowed hundreds of hepatic genes in H3K9me3-heterochromatin to be derepressed. ZNF695 localizes primarily at LINE repeat elements and at gene introns that were linked to gene expression changes. ZNF695 exhibits nuclear mobility characteristics similar to well-characterized heterochromatin proteins. While most KRAB-ZFPs tested that exhibit diminution in one tissue (liver) did not functionally repress that tissue’s genes in another cell type, our strategy revealed a KRAB-ZFP that can be targeted to allow H3K9me3-heterochromatic genes to be derepressed during cellular reprogramming.

2024-10-31 | GSE208295 | GEO

Genome-wide maps of chromatin state and KAP1 occupancy in KRAB zinc finger protein (KRAB-ZFP) gene cluster KO ES cells and testis

Project description:We have shown that many mouse KRAB-ZFPs target retrotransposons which are generally marked by H3K9me3 and KAP1 in ES cells. To test whether these KRAB-ZFPs are require to establish and maintain repressive chromatin marks at these elements, we performed ChIP-seq with antibodies against KAP1 (2 KRAB-ZFP cluster KOs) and H3K9me3 (5 KRAB-ZFP cluster KOs). We show that KRAB-ZFP targeted retrotransposons show reduced KAP1 binding and H3K9me3 in these KO ES cells. Furthermore, we performed ChIP-seq with antibodies against histone modifications typical for promoters and enhancers in Chr4-cl KO ES cells and testis. We show that, in ES cells, ETn retrotransposons gain signatures of active enhancers which acts on earby gene expression. In testis, a handful of different retrotransposons gain enhancer marks, although to a lesser degree. In conclusion, our data shows that KRAB-ZFPs are required to maintain H3K9me3 at retrotransposons in ES cells and to prevent some retrotransposons of becoming enhancers that affect gene expression patterns.

2019-06-27 | GSE115286 | GEO

Transposable elements and their KRAB-ZFP controllers regulate gene expression in adult tissues

Project description:The tetrapod-restricted KRAB-containing zinc finger proteins (KRAB-ZFPs) are essential early embryonic controllers of transposable elements (TEs), which they repress via their cofactor KAP1 and associated effectors through histone and DNA methylation, a process thought to result in irreversible silencing. Using a target-centered functional screen, we matched several murine TEs with their cognate KRAB-ZFP. This revealed an unexpected level of granularity in their interactions, with KRAB-ZFPs recognizing TEs from more than one subfamily, TEs recruiting more than one KRAB-ZFP, and spatially and temporally differential KRAB-ZFP-mediated regulation of TEs and nearby genes. Most importantly, we discovered that the KRAB/KAP1 system controls TEs in adult tissues, in cell culture and in vivo, where they partner up to regulate the expression of cellular genes. Therefore, TEs and KRAB-ZFPs establish widely active transcription networks that regulate not only development but probably also many physiological events. Given the high degree of species-specificity of both TEs and KRAB-ZFPs, these results have important implications for studying and understanding the biology of higher vertebrates, including humans. Analysis of transcriptional profiles of KAP1 or ZFP932/Gm15446 KO cells or tissues, and ZFP932 and Gm15446 ChIPseq in murine ES and C2C12 cells.

2016-03-15 | E-GEOD-74278 | biostudies-arrayexpress

Transposable elements and their KRAB-ZFP controllers regulate gene expression in adult tissues

2016-03-15 | GSE74278 | GEO

Genome-wide analysis of differential transcription in KRAB-ZFP cluster knock-out ES cells and mouse tissues

Project description:Mammalian genomes encode several hundred Krüppel-associated box zinc finger proteins (KRAB-ZFPs) that bind DNA in a sequence-specific manner through tandem arrays of C2H2-type zinc fingers and repress transcription via KRAB-dependent recruitment of the silencing cofactor KAP1. The KRAB-ZFP family rapidly amplified and diversified in mammals by segmental gene duplications, mutations, and zinc finger rearrangements likely in response to continued transposable element invasions, but the biological functions and in vivo requirement of these proteins has gone largely unexplored. We determined the genomic binding sites of 61 murine KRAB-ZFPs and genetically deleted five large KRAB-ZFP gene clusters encoding more than 100 of the approximately 360 mouse KRAB-ZFPs. We demonstrate that most KRAB-ZFPs bind to specific retrotransposon families and that many of these retrotransposons are transcriptionally activated in KRAB-ZFP cluster KO ESCs, licensing retrotransposon-derived enhancers to activate nearby genes.

2019-06-27 | GSE115288 | GEO

Genome-wide binding patterns of murine KRAB zinc finger proteins

Project description:Mammalian genomes encode several hundred Krüppel-associated box zinc finger proteins (KRAB-ZFPs) that bind DNA in a sequence-specific manner through tandem arrays of C2H2-type zinc fingers and repress transcription via KRAB-dependent recruitment of the silencing cofactor KAP1. The KRAB-ZFP family rapidly amplified and diversified in mammals by segmental gene duplications, mutations, and zinc finger rearrangements likely in response to continued transposable element invasions, but the biological functions and in vivo requirement of these proteins has gone largely unexplored. Here we report the identification of the genome-wide binding profiles of 61 mouse KRAB-ZFPs by overexpression of epitope-tagged transgenes. We found that 51 of these KRAB-ZFPs target at least one retrotransposon group. Interestingly, evolutionary young and still active retrotransposons such as IAP and ETn elements are targeted by several KRAB-ZFPs which are mainly encoded within two gene clusters that are not conserved in any other sequenced species. This indicated that an evolutionary arms race drives the rapid expansion of KRAB-ZFP genes in order to restrict active retrotransposons.

2019-06-27 | GSE115287 | GEO

ChIP-exo of human KRAB-ZNFs transduced in HEK 293T cells and KAP1 in hES H1 cells

Project description:Encoded in the hundreds by the human genome, KRAB-containing zinc finger proteins (KRAB-ZFPs) constitute a rapidly evolving family of transcription factors with largely undefined functions. Here, by a combination of phylogenetic and genomic approaches, we retrace the evolutionary history of KRAB-ZFP genes and define the genomic targets of their human products. Through in silico analysis of 207 vertebrate genomes and chromatin immunoprecipitation / deep sequencing characterization of 257 human KRAB-ZFPs, we identify the root of the family in an early Devonian ancestor of tetrapods, describe its diversity amongst these species, and reveal that the majority of its human members primarily recognize transposable elements. Furthermore, by dissecting the timeline and modalities of interactions between human KRAB-ZFPs and their targets, we provide evidence strongly suggesting that these proteins, rather than just engaged in an evolutionary arms race against transposable elements, exploit these invaders as regulatory platforms for the benefit of the host.

2017-03-06 | GSE78099 | GEO

Genome-wide analysis of DNA methylation in KRAB-ZFP cluster KO ES cells

Project description:We report a retrotransposon-specific loss of CpG methylation in chromosome 4 KRAB-ZFP cluster (Chr4-cl) KO ES cells that are cultivated in conditions that induce DNA hypomethylation. The retrotransposon groups with the strongest DNA methylation loss are the main targets of the KRAB-ZFPs within the deleted gene cluster indicating that these KRAB-ZFPs prevent complete DNA demethylation at retrotransposons during global DNA demethylation.

2019-06-27 | GSE115289 | GEO

ChIP-seq analysis of KAP1 binding and H3K9me3 modifications in mouse T cell progenitors

Project description:Chromatin remodelling at specific genomic loci controls lymphoid differentiation. Here, we investigated the role played in this process by Kruppel-Associated Box (KRAB)- Associated Protein 1 (KAP1), the universal cofactor of KRAB-zinc finger proteins (-ZFPs), a tetrapod-restricted family of transcriptional repressors. T cell-specific Kap1-deleted mice displayed a significant expansion of immature thymocytes, imbalances in CD4+/CD8+ cell ratios and impaired responses to TCR stimulation when compared to littermate KAP1 control mice. Transcriptome and chromatin studies revealed that KAP1 binds T cell-specific cis-acting regulatory elements marked by the H3K9me3 repressive mark and enriched in Ikaros/NuRD complexes. Also, KAP1 directly controls the expression of several genes involved in TCR and cytokine signalling. Among these, regulation of FoxO1 seems to play a major role in this system. Likely responsible for tethering KAP1 to at least part of its genomic targets, a small number of KRAB-ZFPs are selectively expressed in T lymphoid cells. These results reveal the so-far unsuspected yet important role of KAP1-mediated epigenetic regulation in T lymphocyte differentiation and activation. Examination of KAP1 binding sites and H3K9me3-enriched regions in wild type and KAP1 KO mouse thymocytes.

2012-12-16 | E-GEOD-38579 | biostudies-arrayexpress

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Project description:The modulation of chromatin status at specific genomic loci controls lymphoid differentiation. Here, we investigated the role played in this process by KAP1, the universal cofactor of KRAB-containing Zinc Finger Proteins (KRAB-ZFPs), a tetrapod-restricted family of transcriptional repressors. T cell-specific Kap1 knockout mice displayed a significant expansion of immature thymocytes and imbalances in the ratios of mature T cells in the thymus and the spleen, with impaired responses to TCR stimulation. Transcriptome and chromatin studies revealed that KAP1 directly controls the expression of a number of genes involved in TCR and cytokine signalling, among which Traf1 and FoxO1, and is strongly associated with cis-acting regulatory elements marked by the H3K9me3 repressive mark on the genome of thymic T cells. Likely responsible for tethering KAP1 to at least part of its genomic targets, a small number of KRAB/ZFPs are selectively expressed in T lymphoid cells. These results reveal the so far unsuspected yet important role of KRAB/KAP1-mediated epigenetic regulation in T lymphocyte differentiation and activation. Cells were harvested form the thymus of 3 CD4-Cre/Kap1flox (KAP1 KO in the T lineage) mice and 3 wt/Kap1flox littermate controls

2012-12-16 | E-GEOD-34447 | biostudies-arrayexpress

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