The Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger
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ABSTRACT:
PROVIDER: PRJNA1001808 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25502048_1.fastq.gz | Fastqsanger.gz | |||
| SRR25502048_2.fastq.gz | Fastqsanger.gz | |||
| SRR25502049_1.fastq.gz | Fastqsanger.gz | |||
| SRR25502049_2.fastq.gz | Fastqsanger.gz | |||
| SRR25502050_1.fastq.gz | Fastqsanger.gz |
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Project description:From a forward genetic screen in zebrafish, we identified the transcription factor, ZBTB11, as critical for basal and emergency granulopoiesis and showed that ZBTB11 sits in a pathway directly downstream of master myeloid regulators including PU.1, GFI1 and CEBPa. To better understand target genes regulated by Zbtb11, RNAseq profiling was performed in neutrophils from WT and Zbtb11 mutant zebrafish.
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Project description:In response to infection and injury, the neutrophil population rapidly expands and then quickly re-establishes the basal state when inflammation resolves. The exact pathways governing neutrophil/macrophage lineage outputs from a common granulocyte-macrophage progenitor are still not completely understood. From a forward genetic screen in zebrafish, we identify the transcriptional repressor, ZBTB11, as critical for basal and emergency granulopoiesis. ZBTB11 sits in a pathway directly downstream of master myeloid regulators including PU.1, and TP53 is one direct ZBTB11 transcriptional target. TP53 repression is dependent on ZBTB11 cys116, which is a functionally critical, metal ion-coordinating residue within a novel viral integrase-like zinc finger domain. To our knowledge, this is the first description of a function for this domain in a cellular protein. We demonstrate that the PU.1-ZBTB11-TP53 pathway is conserved from fish to mammals. Finally, Zbtb11 mutant rescue experiments point to a ZBTB11-regulated TP53 requirement in development of other organs.
| S-EPMC5384227 | biostudies-literature
Project description:Zbtb11 is an uncharacterised transcription factor that is conserved in vertebrates. Mutations in its human gene cause a form of inherited intellectual disablity, while in zebrafish Zbtb11 mutations lead to impaired hematopoesis and neruonal development. We used a combination of functional genomics approaches to determine its functions. To determine the genomic Zbtb11 binding locations, we carried out ChIP-seq using FLAG antibodies in a cell line with the endogenous Zbtb11 N-terminally tagged with FLAG (Zbtb11 FLAG/FLAG), as well as using an anti-Zbtb11 antibody in a wild type line. To determine the genes regulated by Zbtb11 we generated an inducible KO line (Zbtb11 lox/lox, Rosa26 ERt2-Cre) that allows the rapid depletion of Zbtb11 upon treatment with 4-hydroxytamoxyfen (4OHT). We treated Zbtb11 lox/lox, Rosa26 ERt2-Cre cells either with 4OHT (Zbtb11 KO) or ethanol (EtOH) as control, and subsequently performed directional RNA-seq from samples collected 48 hours post-treatment. As control for the effect of 4OHT on gene expression, we also compared Zbtb11 KO cells to wild type cells treated with 4OHT. The two ChIP-seq approaches showed very good overlap and allowed us to generate a set of high-confidence Zbtb11 binding sites common to both peak sets. We found Zbtb11 preferentially binds to a subset of house-keeping genes among which genes encoding proteins with mitochondrial functions are enriched. Upon Zbtb11 deletion, 154 genes changed expression 48 hours later, the vast majority of them down-regulated. Integration of ChIP-seq and RNA-seq data allowed us to identify the genes directly regulated by Zbtb11, and these were significantly enriched in genes with mitochondrial functions, with respiratory complex I and mitoribosome biogenesis being the overrepresented pathways. Subsequent biochemical experiments confirmed Zbtb11 is required for respiratory complex I assembly and for mitochondrial translation. In agreement with these findings Zbtb11 KO led to impaired respiration, proliferation arrest and cell death.
2020-01-14 | GSE125047 | GEO
Project description:Zbtb11 is a transcription factor conserved in vertebrates. Mutations in its human gene cause a form of inherited intellectual disablity, while in zebrafish Zbtb11 mutations lead to impaired hematopoesis and neruonal development. To determine the genes regulated by Zbtb11 we generated an inducible KO ES cell line (Zbtb11 lox/lox, Rosa26 ERt2-Cre) that allows the rapid depletion of Zbtb11 upon treatment with 4-hydroxytamoxyfen (4OHT). We subsequently performed RNA-seq in Zbtb11 KO and control cells to determine differentially expressed genes. Upon Zbtb11 deletion 310 genes changed expression. Integration of the RNA-seq data with Zbtb11 ChIP-seq data (GEO series GSE125047) allowed us to distinguish between genes directly regulated by Zbtb11 and indirect changes. 204 differentially expressed genes were bound by Zbtb11, while 106 did not have Zbtb11 binding sites. Directly regulated genes were significantly enriched in genes with mitochondrial functions, while indirectly controlled genes were enriched for p53 targets. In agreement with these findings Zbtb11 KO led to impaired respiration, proliferation arrest and cell death.
2022-12-31 | GSE130292 | GEO
Project description:Integrase CLIP-seq experiments were conducted on wild-type and eccentric HIV-1 virions generated in the presence of allosteric integrase inhibitors and IN K264/266A and R269/K273A mutations Integrase CLIP-seq experiments were conducted by immunoprecipitation of integrase-RNA complexes from fully formed mature and eccentric virus particles. Libraries of RNA molecules bound by integrase were generated and sequenced by Illumina Hi-Seq2000 and 2500 platforms.
2016-08-25 | E-GEOD-83588 | biostudies-arrayexpress
Project description:ZBTB11 binding genes in NCI-H1299
2023-12-21 | GSE206958 | GEO
Project description:Integrase CLIP-seq experiments were conducted on wild-type and eccentric HIV-1 virions generated in the presence of allosteric integrase inhibitors and IN K264/266A and R269/K273A mutations
2016-08-25 | GSE83588 | GEO
Project description:To determined ZBTB11 and SET regulates genes in NCI-H1299, we esteblished NCI-H1299 cell lines in which ZBTB11 and SET has been knocked down by si-RNA. We then conducted differential expressed genes analysis using data generated form RNA-seq of H1299 cell lines at the condition of two genes knocked down.
2023-12-21 | GSE206957 | GEO
Project description:We have used a conditional mouse model to investigate the role of Zbtb11 specifically in hematopoiesis. When Zbtb11 was deleted in the hematopoietic compartment, embryos died at embryonic day E18.5 with hematopoietic failure. Zbtb11 hematopoietic knockout (Zbtb11hKO) hematopoietic stem cells (HSCs) were overabundantly specified at E14.5 through E17.5 compared to controls. Overspecification was accompanied by loss of stemness, inability to differentiate into committed progenitors and mature lineages in fetal liver, failure to seed fetal bone marrow and total hematopoietic failure. Zbtb11hKO HSCs did not proliferate in vitro and were constrained in cell cycle progression, demonstrating a cell-intrinsic role for Zbtb11 in proliferation and cell cycle regulation in mammalian HSCs. scRNAseq analysis identified Zbtb11-deficient HSCs were underrepresented in an erythroid-primed subpopulation and showed downregulation of oxidative phosphorylation (OXPHOS) pathways and dysregulation of genes associated with the hematopoietic niche. We have identified a cell-intrinsic requirement for Zbtb11-mediated gene regulatory networks in sustaining a pool of maturation-capable hematopoietic stem and progenitor cells.
2023-08-10 | GSE240459 | GEO
Project description:Aims Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that is characterized by progressive fibro-fatty replacement of the myocardium, arrhythmias, and sudden death. While myocardial degeneration and fibro-fatty replacement occurs in specific locations, the underlying molecular changes remain poorly characterized. Here we aim to delineate local changes in gene expression to help identify new genes or pathways that are relevant for specific remodelling processes occurring during ACM. Methods and Results Using Tomo-Seq, a genome-wide transcriptional profiling with high spatial resolution, we created a transmural epicardial to endocardial gene expression atlas of an explanted ACM heart to gain molecular insights into disease-driving processes. This enabled us to link gene expression profiles to the different regional remodelling responses and allowed us to identify genes that are potentially relevant for disease progression. In doing we revealed BTB (broad-complex, tramtrack, bric-à-brac) domain containing 11 (ZBTB11) to be specifically enriched at sites of active fibrofatty replacement of myocardium. Immunohistochemistry indicated ZBTB11 to be enriched in cardiomyocytes flanking fibrofatty areas, which could be confirmed in multiple cardiomyopathy patients. Forced overexpression of ZBTB11 in iPS-derived cardiomyocytes showed ZBTB11 to function as a potent inducer of cardiomyocyte atrophy. Conclusion By combining spatial transcriptomics with classical histological approaches we identified gene expression changes underlying local remodelling responses in ACM. In doing so we found ZBTB11 to function as a relevant driver of cardiomyocyte atrophy. These data show the power of Tomo-Seq to unveil new molecular mechanisms and indicate ZBTB11 as a potential new target for cardiomyopathy.
2021-05-22 | GSE114770 | GEO