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Downregulation of KRAB zinc finger proteins in 5-fluorouracil resistant colorectal cancer cells

ABSTRACT: The radio-chemotherapy with 5-fluorouracil (5-FU) is the standard of care treatment for patients with locally advanced rectal cancer (LARC) but it is only effective for a third of them. The proteomic and transcriptomic response of three colorectal cancer (CRC) cell lines to 5-FU and radiation was assessed and correlated with their genetic background. The induction of a 5-FU-resistance in those cell lines negatively affects the levels of transcripts corresponding to Krüppel-associated box (KRAB)-containing zinc finger proteins (ZFPs), the largest family of transcriptional repressors. Among nearly 350 KRAB-ZFPs, almost a quarter are down-regulated after the induction of a 5-FU-resistance including a common one between the three CRC cell lines, ZNF649, whose role is still unknown. This proteomic, transcriptomic and genomic analysis of intrinsic and acquired resistance highlights possible new mechanisms involved in resistance to treatment and therefore potential new therapeutic targets to overcome this resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153412 | GEO | 2022/04/13

REPOSITORIES: GEO

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Downregulation of KRAB zinc finger proteins in 5-fluorouracil resistant colorectal cancer cells

Project description:The radio-chemotherapy with 5-fluorouracil (5-FU) is the standard of care treatment for patients with locally advanced rectal cancer (LARC) but it is only effective for a third of them. The proteomic and transcriptomic response of three colorectal cancer (CRC) cell lines to 5-FU and radiation was assessed and correlated with their genetic background. The induction of a 5-FU-resistance in those cell lines negatively affects the levels of transcripts corresponding to Krüppel-associated box (KRAB)-containing zinc finger proteins (ZFPs), the largest family of transcriptional repressors. Among nearly 350 KRAB-ZFPs, almost a quarter are down-regulated after the induction of a 5-FU-resistance including a common one between the three CRC cell lines, ZNF649, whose role is still unknown. This proteomic, transcriptomic and genomic analysis of intrinsic and acquired resistance highlights possible new mechanisms involved in resistance to treatment and therefore potential new therapeutic targets to overcome this resistance.

2022-05-19 | PXD020000 | Pride

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

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

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 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

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

The post-translational modifications and translation-regulatory role of METTL14 in 5-fluorouracil-resistant colorectal cancer [Ribo-seq]

Project description:5-fluorouracil (5‑FU) based chemotherapy is the first-line chemotherapy scheme for CRC, whereas acquired drug resistance poses a huge obstacle to curing CRC patients and the mechanism is still obscure. METTL14 is a core subunit of the m6A methyltransferase complex and has been reported to regulate the drug resistance of cancers. Here, we demonstrated that METTL14 is significantly downregulated in 5-FU-resistant CRC and METTL14 overexpression inhibits the proliferation and 5-FU resistance of CRC cells in vitro and in vivo. In addition, we found that MIB1 catalyzes the K63-linked ubiquitination of METTL14 and induces its degradation through the autolysosome pathway, while AURKA-mediated phosphorylation enhances METTL14 stability by inhibiting its ubiquitination. Moreover, we first discovered that METTL14 functions in 5-FU-resistant CRC cells by directly participating in the translation initiation of non-m6A-modified mRNAs independently of METTL3, rather than cooperating with METTL3 to methylate adenosine residues of targets. Further analysis indicated that METTL14 regulates the cell cycle process in 5-FU-resistant CRC cells. Collectively, our study not only identified METTL14 as a potential therapeutic target for 5-FU resistance in CRC but also revealed a novel translation-facilitating role of METTL14.

2023-12-01 | GSE219172 | GEO

The post-translational modifications and translation-regulatory role of METTL14 in 5-fluorouracil-resistant colorectal cancer [mRNA-seq]

2023-12-01 | GSE219171 | 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

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