Primate-restricted KRAB zinc finger proteins control gene expression in human brain
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ABSTRACT:
PROVIDER: PRJNA602996 | ENA |
REPOSITORIES: ENA
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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
Project description:Adaptive evolution of gene promoters driven by primate-specific KRAB zinc finger proteins
| PRJNA830860 | ENA
Project description:Half of all human transcription factors use C2H2 zinc finger domains to specify site-specific DNA binding and yet very little is known about their role in gene regulation. Based on in vitro studies, a zinc finger code has been developed that predicts a binding motif for a particular zinc finger factor (ZNF). However, very few studies have performed genome-wide analyses of ZNF binding patterns and thus it is not clear if the binding code developed in vitro will be useful for identifying target genes of a particular ZNF. We performed genome-wide ChIP-seq for ZNF263, a C2H2 ZNF that contains 9 finger domains, a KRAB repression domain, and a SCAN domain and identified more than 5000 binding sites in K562 cells. Our results suggest that ZNF263 binds to a 24 nt site which differs from the motif predicted by the zinc finger code in several positions. Interestingly, many of the ZNF263 binding sites are located within the transcribed region of the target gene. Although ZNFs containing a KRAB domain are thought to function mainly as transcriptional repressors, many of the ZNF263 target genes are expressed at high levels. To address the biological role of ZNF263, we identified genes whose expression was altered by treatment of cells with ZNF263-specific siRNAs. Our results suggest that ZNF263 can have both positive and negative effects on transcriptional regulation of its target genes. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf Examination of ZNF263 ChIP-seq in K562 cells.
2009-12-03 | E-GEOD-19235 | biostudies-arrayexpress
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
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
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
Project description:A novel KRAB zinc finger gene has changed the balance of HES1 autoregulation during primate evolution
| PRJNA701019 | ENA
Project description:Half of all human transcription factors use C2H2 zinc finger domains to specify site-specific DNA binding and yet very little is known about their role in gene regulation. Based on in vitro studies, a zinc finger code has been developed that predicts a binding motif for a particular zinc finger factor (ZNF). However, very few studies have performed genome-wide analyses of ZNF binding patterns and thus it is not clear if the binding code developed in vitro will be useful for identifying target genes of a particular ZNF. We performed genome-wide ChIP-seq for ZNF263, a C2H2 ZNF that contains 9 finger domains, a KRAB repression domain, and a SCAN domain and identified more than 5000 binding sites in K562 cells. Our results suggest that ZNF263 binds to a 24 nt site which differs from the motif predicted by the zinc finger code in several positions. Interestingly, many of the ZNF263 binding sites are located within the transcribed region of the target gene. Although ZNFs containing a KRAB domain are thought to function mainly as transcriptional repressors, many of the ZNF263 target genes are expressed at high levels. To address the biological role of ZNF263, we identified genes whose expression was altered by treatment of cells with ZNF263-specific siRNAs. Our results suggest that ZNF263 can have both positive and negative effects on transcriptional regulation of its target genes.
2009-11-24 | GSE19146 | GEO
Project description:Genome-wide binding patterns of murine KRAB zinc finger proteins
| PRJNA474488 | ENA
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