DDX6 undergoes phase separation to modulate metabolic plasticity and drug resistance in AML
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ABSTRACT:
PROVIDER: PRJNA1165158 | ENA |
REPOSITORIES: ENA
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Project description:DDX6 is a member of the DEAD-box helicase and it is highly expressed in acute myeloid leukemia (AML). The Knockout (KO) of DDX6 in AML cells significantly suppressed their growth, reduced their mitochondrial oxidative phosphorylation (OXPHOS) in vitro, and substantially delayed leukemogenesis in vivo. To delineate the molecular mechanism through which DDX6 exerts its biological functions in AML, we conducted transcriptome-wide RNA sequencing with Mono-mac-6 AML cells following DDX6 KO.
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Project description:The antagonistic pleiotropy theory of aging proposes that genes enhancing fitness in early life limit lifespan, but the molecular evidence remains underexplored. By profiling translatome changes in Caenorhabditis elegans during starvation recovery, we demonstrate that an open reading frame (ORF) trl-1 'hidden' within an annotated pseudogene significantly translates upon refeeding. trl-1 mutant animals increase brood sizes but shorten lifespan and specifically impair the germline deficiency-induced longevity. The loss of trl-1 abnormally upregulates the translation of vitellogenin that produces copious yolk to provision eggs, whereas vitellogenin overexpression is known to reduce lifespan. We show that TRL-1 protein undergoes liquid-liquid phase separation, through which TRL-1 granules recruit vitellogenin mRNA and inhibit its translation. These results indicate that trl-1 functions as an antagonistic pleiotropic gene to regulate the reproduction-longevity tradeoff by optimizing nutrient production for the next generation.
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Project description:Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, but the underlying molecular mechanisms remain largely unclear. The transcription factor SP1 plays a crucial role in the development of various cancers, including LUAD. Recent studies have indicated that master transcription factors may form phase-separated macromolecular condensates to promote super-enhancer assembly and oncogene expression. In this study, we demonstrated that SP1 undergoes phase separation and that its zinc finger 3 in the DNA binding domain is essential for this process. Through CUT&RUN using antibodies against SP1 and H3K27ac, we discovered a significant correlation between SP1 enrichment and super-enhancer elements, identified the regulator of G protein signaling 20 (RGS20) gene as the most likely target regulated by SP1 through super-enhancer mechanisms, and verified this finding using different approaches. The oncogenic activity of SP1 relies on its phase separation ability and RGS20 gene activation, which can be abolished by GSK-J4, a demethylase inhibitor. Together, our findings provide the first evidence that SP1 regulates its target oncogene expression through phase separation and super-enhancer mechanisms, thereby promoting LUAD cell progression. This study also revealed a novel target for LUAD therapies through intervening in SP1-mediated super-enhancer formation.
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Project description:We performed a genome-scale screen for suppressors of interferon stimulated gene (ISG) expression in human haploid cells (HAP1). DEAD-box helicase 6 (DDX6) was a significant hit. In order to validate DDX6 as a regulator of ISG expression, we created knockouts of DDX6 in HAP1 cells using CRISPR-Cas9 and performed RNA-seq on coding RNA from DDX6 KO and WT cells. This data was used to determine if ISGs were upregulated in DDX6 KO HAP1 cells.
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Project description:Promoter R-loops Recruit U2AF1 to Modulate Its Phase Separation and RNA Splicing
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Project description:SP1 undergoes phase separation and activates RGS20 expression through super-enhancers to promote lung adenocarcinoma progression (CUT＆RUN)
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