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A novel KRAB zinc finger gene has changed the balance of HES1 autoregulation during primate evolution

ABSTRACT: A novel KRAB zinc finger gene has changed the balance of HES1 autoregulation during primate evolution

PROVIDER: PRJNA701019 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13669162_1.fastq.gz	Fastqsanger.gz
	SRR13669162_2.fastq.gz	Fastqsanger.gz
	SRR13669163_1.fastq.gz	Fastqsanger.gz
	SRR13669163_2.fastq.gz	Fastqsanger.gz
	SRR13669164_1.fastq.gz	Fastqsanger.gz

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A novel KRAB zinc finger gene has changed the balance of HES1 autoregulation during primate evolution

Project description:KRAB zinc finger (KZNF) proteins are a class of transcriptional repressors important for epigenetic silencing of specific genomic regions. About 170 primate-specific KZNFs are present in the human genome. While KZNFs are primarily associated with repressing retrotransposon-derived DNA, evidence is emerging that they can be co-opted for other gene regulatory processes. We focused on the 19p12 locus, which shows copy-number variations associated with neurodevelopmental disorders, implying it is required for human brain development. The two genes in this locus, ZNF675 and ZNF681, arose via duplication in primates. Genetic deletion of ZNF675 caused developmental defects in cortical organoids and our data suggest that the observed neurodevelopmental phenotype is mediated by ZNF675 binding to the promoter of the neurodevelopmental gene HES1. We show that ZNF675 interferes with HES1 auto-inhibition, a process essential for maintenance of neural progenitors. As a striking example of how some KZNFs have integrated into pre-existing gene expression networks, these findings suggest the emergence of ZNF675 has caused a change in balance of HES1 autoregulation. The association of ZNF675 CNV with human developmental disorders suggests that this new balance has become essential for normal human brain development.

2021-02-10 | GSE166471 | GEO

A novel KRAB zinc finger gene has changed the balance of HES1 autoregulation during primate evolution

Project description:A novel KRAB zinc finger gene has changed the balance of HES1 autoregulation during primate evolution

| PRJNA701019 | ENA

Project description:A novel KRAB zinc finger gene has changed the balance of HES1 autoregulation during primate evolution

| PRJNA700073 | ENA

KRAB Zincfinger Interactome - The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification

Project description:Krüppel-associated box (KRAB)-containing zinc finger proteins (KZFPs) represent the largest family of human transcription factors. The majority of its members bind to Transposable Elements (TEs), which they repress through the recruitment of the repressor KAP1 to their conserved KRAB domain. In addition to this recognized role, some KZFPs seem to favor different types of loci such as transcription start sites or display diverse functions such as imprinting and gene regulation. Intriguingly, a subset of KZFPs was shown not to recruit the corepressor KAP1. Therefore, we sought to get a better picture of KZFPs putative roles and their association with KAP1. In order to do so, we generated the interactomes of 101 KZFPs through Affinity Purification followed by Mass Spectrometry (AP-MS).

2019-06-04 | PXD011322 | Pride

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

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

Structure and functional mapping of the KRAB-KAP1 repressor complex [KAP1_ChIP-seq]

Project description:We used ChIP-seq to assess how abolition of KRAB binding by KAP1 (through structure-guided mutations in the KAP1-KRAB binding interface) changed the distribution of KAP1 on chromatin genome-wide.

2022-10-10 | GSE215015 | GEO

Structure and functional mapping of the KRAB-KAP1 repressor complex [KAP1_CUT&RUN-seq]

Project description:We used CUT&RUN to assess how abolition of KRAB binding by KAP1 (through structure-guided mutations in the KAP1-KRAB binding interface) changed the distribution of H3K9me3 epigenetic mark genome-wide.

2022-10-10 | GSE215014 | 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

Primate-restricted KRAB zinc finger proteins control gene expression in human brain

Project description:Primate-restricted KRAB zinc finger proteins control gene expression in human brain

| PRJNA602996 | ENA