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The KRAB-ZFP/TRIM28 system exploits transposons to sharpen lineage-specific and activation-induced transcription in human adult T lymphocytes [ChIP-seq]

ABSTRACT: Transposable elements (TEs) are subjected to early embryonic repression through sequence-specific recruitment of KRAB zinc finger proteins (KRAB-ZFPs), their cofactor TRIM28 and associated chromatin modifiers. This prevents transposition and modulates TE-induced changes of gene expression in embryonic stem cells (ESCs). It leads to DNA methylation, a self-perpetuating modification considered as responsible for the permanent silencing of TEs after this period. Challenging this view, we reveal here that the KRAB/TRIM28 system keeps mediating a highly dynamic control of TEs and TE-mediated transcriptional influences in adult human cells. Using CD4+ T lymphocytes as an experimental model, we first observed that in these cells many TEs are still bound by TRIM28, the recruitment of which is dynamically regulated upon T cell receptor stimulation. Second, we determined that this transition reflects marked changes in the expression patterns of TE-binding KRAB-ZFPs. Finally, we could demonstrate that TRIM28 depletion induces broad transcriptional alterations in T cells, with de-repression notably of TE-based enhancers leading to the illegitimate activation of nearby genes and breaches of lineage-specific transcriptional restrictions. These data contribute to demonstrate that TEs and their KRAB-ZFP/TRIM28 control system are important regulators of gene expression in adult human cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81872 | GEO | 2021/06/01

REPOSITORIES: GEO

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The KRAB-ZFP/TRIM28 system exploits transposons to sharpen lineage-specific and activation-induced transcription in human adult T lymphocytes [RNA-seq]

Project description:Transposable elements (TEs) are subjected to early embryonic repression through sequence-specific recruitment of KRAB zinc finger proteins (KRAB-ZFPs), their cofactor TRIM28 and associated chromatin modifiers. This prevents transposition and modulates TE-induced changes of gene expression in embryonic stem cells (ESCs). It leads to DNA methylation, a self-perpetuating modification considered as responsible for the permanent silencing of TEs after this period. Challenging this view, we reveal here that the KRAB/TRIM28 system keeps mediating a highly dynamic control of TEs and TE-mediated transcriptional influences in adult human cells. Using CD4+ T lymphocytes as an experimental model, we first observed that in these cells many TEs are still bound by TRIM28, the recruitment of which is dynamically regulated upon T cell receptor stimulation. Second, we determined that this transition reflects marked changes in the expression patterns of TE-binding KRAB-ZFPs. Finally, we could demonstrate that TRIM28 depletion induces broad transcriptional alterations in T cells, with de-repression notably of TE-based enhancers leading to the illegitimate activation of nearby genes and breaches of lineage-specific transcriptional restrictions. These data contribute to demonstrate that TEs and their KRAB-ZFP/TRIM28 control system are important regulators of gene expression in adult human cells.

2021-06-01 | GSE81871 | 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

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

Project description:Reverse transcription-derived sequences account for at least half of the human genome. Although these retroelements are formidable motors of evolution, they can occasionally cause disease, and accordingly are inactivated during early embryogenesis through epigenetic mechanisms. In the mouse, at least for endogenous retroviruses, important mediators of this process are the tetrapod-specific KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor TRIM28. The present study demonstrates that KRAB/TRIM28-mediated regulation is responsible for controlling a very broad range of human-specific endogenous retroelements (EREs) in human embryonic stem (ES) cells and that it exerts, as a consequence, a marked effect on the transcriptional dynamics of these cells. It further reveals reciprocal dependence between TRIM28 recruitment at specific families of EREs and DNA methylation. It finally points to the importance of persistent TRIM28-mediated control of ERE transcriptional impact beyond their presumed inactivation by DNA methylation. Analyses of epigentic effectors and marks in KAP1 WT and KD human embryonic stem cells

2014-05-29 | E-GEOD-57989 | biostudies-arrayexpress

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

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

2014-05-29 | GSE57989 | 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

Epigenomic conservation of transposable element silencing [ChIP-seq]

Project description:Transposable elements (TEs) comprise a substantial proportion of primate genomes. Because of the potential deleterious effects of TEs during development, TEs are targeted for silencing by sequence-specific KRAB-ZNF proteins, which recruit the TRIM28-SETDB1 complex, to deposit the repressive histone modification H3K9me3. TEs, in turn, acquire mutations to evade detection by the host, and hence KRAB-ZNF proteins need to rapidly evolve to counteract them. To investigate the short-term evolution of TE silencing, we profiled the genome-wide distribution of H3K9me3 in both human and chimpanzee induced pluripotent stem cells. We performed chromatin immunoprecipitation followed by high-throughput sequencing for H3K9me3, as well as total RNA sequencing in ten human and seven chimpanzee individuals. H3K9me3 enrichment was quantified in 141,642 regions determined to be orthologous between the two species. These H3K9me3-enriched regions were overlaid on a compiled set of 4 million orthologous TEs that can be mapped in both species.

2018-04-26 | GSE96710 | GEO

Epigenomic conservation of transposable element silencing [RNA-seq]

2018-04-26 | GSE96711 | GEO

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