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Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [Nanostring]

ABSTRACT: Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [Nanostring]

PROVIDER: PRJNA952253 | ENA |

REPOSITORIES: ENA

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Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [Nanostring]

Project description:DICER1 canonically regulates micro(mi)RNA-mediated epithelial-to-mesenchymal transition (EMT) in lung adenocarcinomas (LUADs). We discovered that KRAS/ERK pathway phosphorylates DICER1 causing its nuclear translocation; phosphomimetic Dicer1 contributes to tumorigenesis in mice. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. Here, we show that phospho-DICER1 is expressed in invasive human LUADs and promotes late-stage tumor progression in mice with oncogenic Kras, independent of miRNAs and EMT. Strikingly, in mice, we observed that the AT2 tumor cells with phospho-DICER1 express endodermal (gastric) genes and display an open chromatin state such that there are sub-populations of tumors cells with alveolar-endodermal or only endodermal identity. Importantly, we also observed expression of gastric genes in human LUADs with phospho-DICER1. Mechanistically, we identify a chromatin-DICER1 nuclear complex comprised of Mediator complex subunit 12, CBX1, MACROH2A.1 and transcriptional regulators. Together, we propose that phosphorylated-nuclear DICER1 leads to lineage reprogramming of AT2 tumor cells to mediate lung cancer progression.

2023-08-08 | GSE228966 | GEO

Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [ATAC-seq]

2023-08-08 | GSE228964 | GEO

Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [scRNA-seq]

2023-08-08 | GSE228965 | GEO

Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas

Project description:Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas

| PRJNA952250 | ENA

Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [scRNA-seq]

Project description:Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [scRNA-seq]

| PRJNA952254 | ENA

Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [ATAC-seq]

Project description:Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [ATAC-seq]

| PRJNA952255 | ENA

Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-08 | GSE228968 | GEO

Proximity Proteomics Revealed Dicer1 and Transporters as Client Proteins of Aha1

Project description:Co-chaperone Aha1 activates HSP90 ATPase to promote the folding of client proteins. However, the client proteins of Aha1 are largely unknown. By employing ascorbate peroxidase (APEX) based proximity labeling, we identified 32 proximity proteins of HSP90 that are modulated by genetic depletion of Aha1. Among them, Dicer1 is one of the top-ranked proteins, which were further confirmed by streptavidin pull-down followed by Western blot analysis, demonstrating the reliability of the approach. Flag pull-down result showed interactions between endogenous HSP90 and Dicer1 and Aha1. The Dicer1 level is regulated synergistically by Aha1 and HSP90. Maturation-dependent interaction results showed a preferential binding of Aha1 and HSP90 to nascently translated Dicer1. Reconstitution of Aha1-depleted cells with WT Aha1 restored Dicer1 level, while the HSP90-binding-defective E67K mutant exhibited partial restoration. Moreover, knockdown of Aha1 and inhibition of HSP90 can diminish the levels of mature miRNA, let-7b and mir-30a. Overall, our study uncovers, for the first time, Dicer1 and transporter proteins as clients of Aha1 and HSP90.

2022-11-19 | PXD028980 | Pride

Analysis of the impact of DICER1 and DROSHA on the angio-genic capacity of human endothelial cells

Project description:RNAi-mediated knockdown of DICER1 and DROSHA, enzymes critically involved in miRNA biogenesis, has been postulated to affect the homeostasis and the angiogenic capacity of human endothelial cells. To re-evaluate this issue, we reduced the expression of DICER1 or DROSHA by RNAi-mediated knockdown and subsequently investigated the effect of these interventions on the angiogenic capacity of human umbilical vein endothelial cells (HUVEC) in vitro (proliferation, migration, tube formation, endothelial cell spheroid sprouting) and in a HUVEC xenograft assay in immune incompetent NSGTM mice in vivo. In contrast to previous reports, neither knockdown of DICER1 nor knockdown of DROSHA profoundly affected migration or tube formation of HUVEC or the angiogenic capacity of HUVEC in vivo. Furthermore, knockdown of DICER1 and the combined knockdown of DICER1 and DROSHA tended to increase VEGF-induced BrdU incorporation and induced angiogenic sprouting from HUVEC spheroids. Consistent with these observations, global proteomic analyses showed that knockdown of DICER1 or DROSHA only moderately altered HUVEC protein expression profiles but additively reduced, for example, expression of the angiogenesis inhibitor thrombospondin-1. In conclusion, global reduction of miRNA biogenesis by knockdown of DICER1 or DROSHA does not inhibit the angiogenic capacity of HUVEC. Further studies are therefore needed to elucidate the influence of these enzymes in the context of human endothelial cell-related angiogenesis.

2022-02-17 | PXD027923 | Pride

Genomic characterization of DICER1-associated neoplasms uncovers novel molecular classes

Project description:DNA methylation data of a novel group of mesenchymal tumors with DICER1 alteration which includes two novel classes designated “low-grade mesenchymal tumor with DICER1 alteration” (LGMT DICER1) and “high-grade sarcoma with DICER1 alteration” (HGS DICER1), as well as the recently described class of primary intracranial sarcoma, DICER1-mutant (PIS DICER1)

2023-02-08 | GSE214568 | GEO

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