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Hominid-specific transposable elements and KRAB-ZFPs facilitate human embryonic genome activation and transcription in naïve hESCs [ChIP-seq]

ABSTRACT: Transposable elements (TEs) are key to the evolutionary turnover of regulatory sequences. How they can play such an essential role in spite of their genotoxic potential is unknown. Here, we demonstrate that KRABcontaining zinc finger proteins control the timely and pleiotropic engagement of TE-derived cis-regulators of transcription. We first observed that evolutionary recent TEs of the SVA, HERVK and HERVH subgroups are major contributors to chromatin opening during human embryonic genome activation and act as KLF-stimulated enhancers in naïve embryonic stem cells. We then found that KZFPs of corresponding evolutionary ages are simultaneously induced and repress the transcriptional activity of these TEs. We finally determined that the same KZFP-controlled TE-based enhancers later serve as developmental and tissue-specific regulators of gene expression. Thus, by taming the transcriptional impact of TEs during early embryogenesis, KZFPs allow for their genome-wide incorporation into transcriptional networks, thereby contributing to the species-specificity of human genome regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130417 | GEO | 2019/04/30

REPOSITORIES: GEO

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Hominid-specific transposable elements and KRAB-ZFPs facilitate human embryonic genome activation and transcription in naïve hESCs [ATAC-seq]

Project description:Transposable elements (TEs) are key to the evolutionary turnover of regulatory sequences. How they can play such an essential role in spite of their genotoxic potential is unknown. Here, we demonstrate that KRABcontaining zinc finger proteins control the timely and pleiotropic engagement of TE-derived cis-regulators of transcription. We first observed that evolutionary recent TEs of the SVA, HERVK and HERVH subgroups are major contributors to chromatin opening during human embryonic genome activation and act as KLF-stimulated enhancers in naïve embryonic stem cells. We then found that KZFPs of corresponding evolutionary ages are simultaneously induced and repress the transcriptional activity of these TEs. We finally determined that the same KZFP-controlled TE-based enhancers later serve as developmental and tissue-specific regulators of gene expression. Thus, by taming the transcriptional impact of TEs during early embryogenesis, KZFPs allow for their genome-wide incorporation into transcriptional networks, thereby contributing to the species-specificity of human genome regulation.

2019-04-30 | GSE130418 | GEO

Hominid-specific transposable elements and KRAB-ZFPs facilitate human embryonic genome activation and transcription in naïve hESCs [RNA-seq]

2019-04-30 | GSE130416 | GEO

Chip-exo and Chip-seq of human KRAB-ZNFs transduced in HEK 293T cells

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 more than 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.

2023-06-15 | GSE200964 | GEO

Individual retrotransposon integrants are differentially controlled by KZFP/KAP1-dependent histone methylation, DNA methylation and TET-mediated hydroxymethylation in naïve embryonic stem cells

Project description:The KZFP/KAP1 (KRAB zinc finger proteins/KRAB-associated protein 1) system plays a central role in the silencing of transposable elements (TEs) and the maintenance of parent-of-origin DNA methylation at imprinting control regions (ICRs) during the wave of genome-wide reprogramming that precedes implantation. In naïve murine embryonic stem cells (mESCs), the genome is maintained highly hypomethylated by a combination of active demethylation (operated by TET proteins) and lack of de novo methylation; in these cells, KAP1 is tethered by sequence-specific KZFPs to ICRs and TEs where it recruits histone and DNA methyltransferases to impose heterochromatin formation and DNA methylation. Here, upon removing either KAP1 or the cognate KZFP, we observed rapid TET-dependent accumulation of 5hmC at both ICRs and TEs. In absence of the KZFP/KAP1 complex, ICRs lost heterochromatic histone marks and underwent both active and passive DNA demethylation. Using RNA-seq, we further compared the expression profiles of TEs upon Kap1 removal in wild type, Dnmt and Tet triple knockout mESCs. We found that KAP1 represents the main effector of TEs repression in all three settings, yet we could additionally identify specific groups of TEs also controlled by DNA methylation. Furthermore, activation upon Kap1 removal in the absence of TET proteins could be either blunted or increased depending on TE subsets, indicating a complex interplay between heterochomatin and active demethylation in regulating the expression of the endovirome.

2018-02-28 | GSE95720 | GEO

ARID1A loss derepresses human endogenous retrovirus-H to modulate BRD4-dependent transcription

Project description:Purpose: The transposable elements (TEs) through evolutionary exaptation have become an integral part of human genome, offering ample regulatory sequences and shaping chromatin 3D architecture. While the functional impacts of TE-derived sequences on early embryogenesis are recognized, their role in malignancy has only started to emerge. Results: Here we show that many TEs, especially the pluripotency-related endogenous retrovirus H (HERVH), are abnormally activated in colorectal cancer (CRC) samples. The transcriptional upregulation of HERVH is associated with mutations of several tumor suppressors including ARID1A. Knockout of ARID1A in CRC cells leads to increased accessibility at HERVH loci and enhanced transcription, which is dependent on ARID1B. Suppression of HERVH in CRC cells and patient-derived organoids impairs tumor growth. Mechanistically, HERVH transcripts colocalize with nuclear BRD4 foci, modulate their dynamics, and co-regulate many target genes. Conclusions: Altogether, we uncover a critical role for ARID1A in restraining HERVH, which can promote tumorigenesis by stimulating BRD4-dependent transcription when ARID1A is mutated.

2021-07-21 | GSE180475 | GEO

Genetic deletion of ZNF91 in human embryonic stem cells leads to ectopic activation of SVAs and collective upregulation of KRAB zinc finger gene clusters

Project description:Transposable element (TE) invasions have shaped vertebrate genomes over the course of evolution. They have contributed an extra layer of species-specific gene regulation by providing novel transcription factor binding sites. In humans, SVA elements are one of three still active TE families, and approximately 2800 SVA insertions exist in the human genome, half of which are human-specific. TEs are often silenced by KRAB zinc finger (KZNF) proteins recruiting co-repressor proteins that establish a repressive chromatin state. A number of KZNFs have been reported to bind SVAs, but their individual contribution to repressing SVAs and their roles in suppressing SVA-mediated gene-regulatory effects remains elusive. We analyzed the genome-wide binding profile for ZNF91 in human cells and found that ZNF91 interacts with the VNTR region of SVAs. Through CRISPR-Cas9 mediated deletion of ZNF91 in human embryonic stem cells we established that loss of ZNF91 results in increased transcriptional activity of SVAs. In contrast, SVA activation was not observed upon genetic deletion of the ZNF611 gene encoding another strong SVA-interactor. Epigenetic profiling confirmed the loss of SVA repression in the absence of ZNF91 and revealed that mainly evolutionary young SVAs gain gene activation-associated epigenetic modifications. Genes close to activated SVAs showed a mild upregulation, indicating SVAs adopt properties of cis-regulatory elements in the absence of repression. Intriguingly, genome-wide de-repression of SVAs elicited the communal upregulation of KZNFs that reside in KZNF clusters. This phenomenon may provide new insights into the potential mechanisms utilized by the host genome to sense and counteract TE invasions.

2021-01-28 | GSE162571 | GEO

Identification of potential target genes of KRAB zinc-finger proteins in cancer cells

Project description:KRAB zinc-finger proteins (KZFPs) are potent transcriptional suppressors and suspected to be associated with cancer progression. To identify the potential target genes of KZFPs in lung adenocarcinoma cells, we established a panel of A459 cell lines that over-express 30 types of KZFPs (A549/KZFP cells) and performed RNA-sequencing (RNA-Seq) analysis of these cells.

2020-09-29 | GSE141802 | GEO

The transposable element composition of human lincRNAs reveals a role for HERVH elements to promote stem cell specific expression of lincRNAs

Project description:Numerous studies over the past decade have elucidated a substantial set of long intergenic noncoding RNAs (lincRNAs). It has since become clear that lincRNAs constitute an important layer of genome regulation across a wide spectrum of species. Yet, the factors governing their evolution and origins remain relatively unexplored. One possible factor that may have shaped lincRNA biology are transposable elements (TEs). Here we set out to comprehensively characterize the TE content of lincRNAs relative to genomic averages and protein coding transcripts. Our analysis of the TE composition across 9241 human lincRNAs revealed that, in sharp contrast to protein coding genes, a striking majority (83%) of lincRNAs contain a TE, and TEs comprise 42% of lincRNA transcript sequences. LincRNA TE composition varies significantly from genomic averages, being depleted of LI and Alu elements and enriched for a broad class of endogenous retroviruses (ERVs). Furthermore, specific TE families occur in biased positions and orientations within lincRNAs, particularly at their transcription start sites, suggesting a role in the origin of those lincRNAs. Finally, we find that TEs can drive gene expression regulation of lincRNAs—we observed a dramatic correlation between lincRNAs containing HERVH elements and almost exclusive expression in pluripotent cells. Conversely, those lincRNAs that are devoid of TEs are more highly expressed in testis. Collectively, TEs pervade lincRNAs and have shaped lincRNA evolution and function via bestowing tissue-specific expression from donated transcriptional regulatory signals. We extracted profiled the transcriptome expression polyadenylated mRNA-Seq. We then used these to reconstruct the transcriptome using de-novo assemblers and identify long non coding RNAs and their expression.

2013-01-22 | E-GEOD-38993 | biostudies-arrayexpress

KRAB zinc finger proteins ZNF587/ZNF417 protect lymphoma cells from replicative stress-induced inflammation [RNA_D10]

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

KRAB zinc finger proteins ZNF587/ZNF417 protect lymphoma cells from replicative stress-induced inflammation [RNA_D6]

2024-01-18 | GSE229468 | GEO

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