ZNF695 Represses Hepatic Genes and Regulates H3K9me3-Heterochromatin [CUT&RUN]
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ABSTRACT:
PROVIDER: PRJNA853324 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19867322_1.fastq.gz | Fastqsanger.gz | |||
| SRR19867322_2.fastq.gz | Fastqsanger.gz | |||
| SRR19867323_1.fastq.gz | Fastqsanger.gz | |||
| SRR19867323_2.fastq.gz | Fastqsanger.gz | |||
| SRR19867324_1.fastq.gz | Fastqsanger.gz |
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Project description:ZNF695 Represses Hepatic Genes and Regulates H3K9me3-Heterochromatin
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Project description:In any cell type, repetitive elements and alternative lineage genes can be silenced by heterochromatin marked by H3K9me3 and/or H3K27me3. During cellular reprogramming to pluripotency and to liver, genes marked by H3K9me3 are the most difficult to activate. Given that KRAB domain-containing, zinc finger proteins (KRAB-ZFPs) can direct repressive H3K9me3 at genes and transposable elements, we sought to identify KRAB-ZFPs that silence liver genes in non-liver lineages and could be useful for down-regulating during human fibroblast to hepatocyte (hiHep) reprogramming. We identified six KRAB-ZFPs that are essentially not expressed in liver or BJ fibroblasts, but are expressed in many other tissues. We knocked down each KRAB-ZFP during hepatic reprogramming of human fibroblasts and found that only knockdown of primate-specific ZNF695 allowed hundreds of hepatic genes in H3K9me3-heterochromatin to be derepressed. ZNF695 localizes primarily at LINE repeat elements and at gene introns that were linked to gene expression changes. ZNF695 exhibits nuclear mobility characteristics similar to well-characterized heterochromatin proteins. While most KRAB-ZFPs tested that exhibit diminution in one tissue (liver) did not functionally repress that tissue’s genes in another cell type, our strategy revealed a KRAB-ZFP that can be targeted to allow H3K9me3-heterochromatic genes to be derepressed during cellular reprogramming.
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Project description:ZNF695 Represses Hepatic Genes and Regulates H3K9me3-Heterochromatin [RNA-seq]
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Project description:In any cell type, repetitive elements and alternative lineage genes can be silenced by heterochromatin marked by H3K9me3 and/or H3K27me3. During cellular reprogramming to pluripotency and to liver, genes marked by H3K9me3 are the most difficult to activate. Given that KRAB domain-containing, zinc finger proteins (KRAB-ZFPs) can direct repressive H3K9me3 at genes and transposable elements, we sought to identify KRAB-ZFPs that silence liver genes in non-liver lineages and could be useful for down-regulating during human fibroblast to hepatocyte (hiHep) reprogramming. We identified six KRAB-ZFPs that are essentially not expressed in liver or BJ fibroblasts, but are expressed in many other tissues. We knocked down each KRAB-ZFP during hepatic reprogramming of human fibroblasts and found that only knockdown of primate-specific ZNF695 allowed hundreds of hepatic genes in H3K9me3-heterochromatin to be derepressed. ZNF695 localizes primarily at LINE repeat elements and at gene introns that were linked to gene expression changes. ZNF695 exhibits nuclear mobility characteristics similar to well-characterized heterochromatin proteins. While most KRAB-ZFPs tested that exhibit diminution in one tissue (liver) did not functionally repress that tissue’s genes in another cell type, our strategy revealed a KRAB-ZFP that can be targeted to allow H3K9me3-heterochromatic genes to be derepressed during cellular reprogramming.
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Project description:H3K9me3-heterochromatin, compacted by HP1 proteins, restricts transcription factor binding and functions as a barrier to cell fate changes in development and reprogramming1,2. To investigate principles underlying H3K9me3-heterochromatin maintenance in mammalian cells, we applied degron engineering3,4 on mouse ESCs to conditionally deplete all three H3K9me3-methyltransferases within one hour and found an unexpectedly dynamic nature of heterochromatin maintenance. Following H3K9me3 methyltransferases degradation, HP1β dissociates from heterochromatin within three hours, and transcription factors quickly access the de-compacted heterochromatin, activating transcription of their targets, which then promotes H3K9me3 decay. Both passive dilution and active removal contribute to the H3K9me3 decay. Mathematical modeling reveals distinct H3K9me3 heterochromatin states with diverse chromatin features which influence initial H3K9me3 levels and the stability of H3K9me3 domains, thereby expanding our understanding of distinct heterochromatin domains. Rampant transposable element de-repression interferes with transcription of poised early developmental and signaling genes outside H3K9me3-domains, highlighting the intricate roles of dynamic H3K9me3-heterochromatin maintenance in safeguarding developmental programs. Our findings deconvolve the hierarchical relationships between H3K9me3 marks, methyltransferases, HP1 and transcription factors to reveal principles of H3K9me3-heterochromatin maintenance and how its remodeling enables transcription and cell fate change.
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Project description:H3K9me3-heterochromatin, compacted by HP1 proteins, restricts transcription factor binding and functions as a barrier to cell fate changes in development and reprogramming1,2. To investigate principles underlying H3K9me3-heterochromatin maintenance in mammalian cells, we applied degron engineering3,4 on mouse ESCs to conditionally deplete all three H3K9me3-methyltransferases within one hour and found an unexpectedly dynamic nature of heterochromatin maintenance. Following H3K9me3 methyltransferases degradation, HP1β dissociates from heterochromatin within three hours, and transcription factors quickly access the de-compacted heterochromatin, activating transcription of their targets, which then promotes H3K9me3 decay. Both passive dilution and active removal contribute to the H3K9me3 decay. Mathematical modeling reveals distinct H3K9me3 heterochromatin states with diverse chromatin features which influence initial H3K9me3 levels and the stability of H3K9me3 domains, thereby expanding our understanding of distinct heterochromatin domains. Rampant transposable element de-repression interferes with transcription of poised early developmental and signaling genes outside H3K9me3-domains, highlighting the intricate roles of dynamic H3K9me3-heterochromatin maintenance in safeguarding developmental programs. Our findings deconvolve the hierarchical relationships between H3K9me3 marks, methyltransferases, HP1 and transcription factors to reveal principles of H3K9me3-heterochromatin maintenance and how its remodeling enables transcription and cell fate change.
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Project description:H3K9me3-heterochromatin, compacted by HP1 proteins, restricts transcription factor binding and functions as a barrier to cell fate changes in development and reprogramming1,2. To investigate principles underlying H3K9me3-heterochromatin maintenance in mammalian cells, we applied degron engineering3,4 on mouse ESCs to conditionally deplete all three H3K9me3-methyltransferases within one hour and found an unexpectedly dynamic nature of heterochromatin maintenance. Following H3K9me3 methyltransferases degradation, HP1β dissociates from heterochromatin within three hours, and transcription factors quickly access the de-compacted heterochromatin, activating transcription of their targets, which then promotes H3K9me3 decay. Both passive dilution and active removal contribute to the H3K9me3 decay. Mathematical modeling reveals distinct H3K9me3 heterochromatin states with diverse chromatin features which influence initial H3K9me3 levels and the stability of H3K9me3 domains, thereby expanding our understanding of distinct heterochromatin domains. Rampant transposable element de-repression interferes with transcription of poised early developmental and signaling genes outside H3K9me3-domains, highlighting the intricate roles of dynamic H3K9me3-heterochromatin maintenance in safeguarding developmental programs. Our findings deconvolve the hierarchical relationships between H3K9me3 marks, methyltransferases, HP1 and transcription factors to reveal principles of H3K9me3-heterochromatin maintenance and how its remodeling enables transcription and cell fate change.
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Project description:The structural organization of eukaryotic genomes is contingent upon fractionation of DNA into transcriptionally active euchromatin and repressive heterochromatin. However, we still have a limited understanding of how these distinct states are first established during animal embryogenesis. Histone lysine 9 trimethylation (H3K9me3) is critical to heterochromatin formation and bulk establishment of this mark is thought to help drive large-scale remodeling of the initially naive chromatin state during animal embryogenesis. However, a detailed understanding of this process is lacking. Here, we leverage CUT&RUN to define the emerging H3K9me3 landscape of the zebrafish embryo with high sensitivity and temporal resolution. We find that despite the prevalence of DNA transposons in the zebrafish genome, LTR transposons are preferentially targeted for H3K9me3 deposition in the embryo, with different families showing distinct establishment kinetics. High signal-to-noise ratios afforded by CUT&RUN revealed emerging sites of low-amplitude H3K9me3 nucleation prior embryonic genome activation (EGA), with early nucleation primarily at a subset of transposon sequences, loci enriched for maternal piRNAs, and pericentromeres. Unexpectedly, the number of nucleated H3K9me3 sites increases linearly across blastula development while quantitative comparison revealed a >10-fold genome-wide increase in H3K9me3 signal at established sites over just 30 minutes precisely at the onset of major EGA. Later stage analysis revealed continued maturation of the H3K9me3 landscape beyond the initial wave of bulk establishment. Our findings uncover distinct mechanisms of pre- and post-EGA H3K9me3 targeting and reveal decoupling of H3K9me3 establishment from reinforcement during de novo heterochromatin formation.
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