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Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246419 | GEO | 2025/07/07

REPOSITORIES: GEO

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Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control

Project description:The synthesis of proteins in multicellular organisms needs to be carefully tuned to changing proteome demands during development, and defects in this process often have a disproportionate impact in specific cell types and tissues. Here, we compared the essentiality of 262 genes from the mRNA translation machinery by inducible CRISPRi screens in HEK293 cells, human induced pluripotent stem cells (hiPSC) and hiPSC-derived neuronal progenitor cells, neurons, and cardiomyocytes. While ribosomal proteins and core translation factors were broadly essential, the cellular responses and phenotypic consequences of perturbing translation-dependent quality control pathways were highly dependent on the cellular context. By profiling ribosome occupancy in cells that are particularly sensitive to ZNF598 loss, we discovered a previously unappreciated role of this protein in detecting ribosome collisions during translation initiation. Our findings illuminate the importance of cell identity for deciphering the molecular mechanisms of translational control in metazoans.

2025-07-07 | GSE246212 | GEO

Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control

Project description:The translation of mRNA into proteins in multicellular organisms needs to be carefully tuned to changing proteome demands in development and differentiation, and defects in translation often have a disproportionate impact in distinct cell types. Here we used inducible CRISPR interference screens to compare the essentiality of genes with functions in mRNA translation in human induced pluripotent stem cells (hiPSC) and hiPSC-derived neural and cardiac cells. We find that core components of the mRNA translation machinery are broadly essential, but the consequences of perturbing translation-coupled quality control factors are highly cell type dependent. Human stem cells critically depend on pathways that detect and rescue slow or stalled ribosomes, and on the E3 ligase ZNF598 to resolve a novel type of ribosome collisions at translation start sites on endogenous mRNAs with highly efficient initiation. Our findings underscore the importance of cell identity for deciphering the molecular mechanisms of translational control in metazoans.

2025-07-07 | GSE246418 | GEO

Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control [sgRNA]

2025-07-07 | GSE246415 | GEO

Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control

Project description:Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control

| PRJNA1032902 | ENA

Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control

Project description:Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control

| PRJNA1032905 | ENA

Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control

Project description:Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control

| PRJNA1032057 | ENA

Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control [sgRNA]

Project description:Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control [sgRNA]

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CRISPRi screens reveal genes modulating yeast growth in lignocellulose hydrolysate.

Project description:BackgroundBaker's yeast is a widely used eukaryotic cell factory, producing a diverse range of compounds including biofuels and fine chemicals. The use of lignocellulose as feedstock offers the opportunity to run these processes in an environmentally sustainable way. However, the required hydrolysis pretreatment of lignocellulosic material releases toxic compounds that hamper yeast growth and consequently productivity.ResultsHere, we employ CRISPR interference in S. cerevisiae to identify genes modulating fermentative growth in plant hydrolysate and in presence of lignocellulosic toxins. We find that at least one-third of hydrolysate-associated gene functions are explained by effects of known toxic compounds, such as the decreased growth of YAP1 or HAA1, or increased growth of DOT6 knock-down strains in hydrolysate.ConclusionOur study confirms previously known genetic elements and uncovers new targets towards designing more robust yeast strains for the utilization of lignocellulose hydrolysate as sustainable feedstock, and, more broadly, paves the way for applying CRISPRi screens to improve industrial fermentation processes.

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Coupled protein quality control during nonsense-mediated mRNA decay.

Project description:Translation of mRNAs containing premature termination codons (PTCs) results in truncated protein products with deleterious effects. Nonsense-mediated decay (NMD) is a surveillance pathway responsible for detecting PTC containing transcripts. Although the molecular mechanisms governing mRNA degradation have been extensively studied, the fate of the nascent protein product remains largely uncharacterized. Here, we use a fluorescent reporter system in mammalian cells to reveal a selective degradation pathway specifically targeting the protein product of an NMD mRNA. We show that this process is post-translational and dependent on the ubiquitin proteasome system. To systematically uncover factors involved in NMD-linked protein quality control, we conducted genome-wide flow cytometry-based screens. Our screens recovered known NMD factors but suggested that protein degradation did not depend on the canonical ribosome-quality control (RQC) pathway. A subsequent arrayed screen demonstrated that protein and mRNA branches of NMD rely on a shared recognition event. Our results establish the existence of a targeted pathway for nascent protein degradation from PTC containing mRNAs, and provide a reference for the field to identify and characterize required factors.

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CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer.

Project description:Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.

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