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: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.
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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.
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Project description:PBK/TOPK is a mitotic kinase implicated in haematological and non-haematological cancers. Here we show that the key haemopoietic regulators Ikaros and Aiolos require PBK-mediated phosphorylation to dissociate from chromosomes in mitosis. Eviction of Ikaros is rapidly reversed by addition of the PBK-inhibitor OTS514, revealing dynamic regulation by kinase and phosphatase activities. To identify more PBK targets, we analysed loss of mitotic phosphorylation events in Pbk–/– preB cells and performed proteomic comparisons on isolated mitotic chromosomes. Among a large pool of C2H2-zinc finger targets, PBK is essential for evicting the CCCTC-binding protein CTCF and zinc finger proteins encoded by Ikzf1, Ikzf3, Znf131 and Zbtb11. PBK-deficient cells were able to divide but showed altered chromatin accessibility and nucleosome positioning consistent with CTCF retention. Our studies reveal that PBK controls the dissociation of selected factors from condensing mitotic chromosomes and contributes to their compaction.
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