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Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma

ABSTRACT: Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma

PROVIDER: PRJNA1122072 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29341200_1.fastq.gz	Fastqsanger.gz
	SRR29341200_2.fastq.gz	Fastqsanger.gz
	SRR29341201_1.fastq.gz	Fastqsanger.gz
	SRR29341201_2.fastq.gz	Fastqsanger.gz
	SRR29341202_1.fastq.gz	Fastqsanger.gz

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Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma [Methylation array]

Project description:Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma [Methylation array]

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Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma [RNA-seq]

Project description:Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma [RNA-seq]

| PRJNA1122074 | ENA

Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma [Methylation array]

Project description:Sonic hedgehog subgroup of medulloblastoma (SHH-MB) is characterized by aberrant activation of the SHH signaling pathway. An inhibition of the positive SHH regulator Smoothened (SMO) has demonstrated promising clinical efficacy. Yet, primary and acquired resistance to SMO inhibitors limit their efficacy. An understanding of underlying molecular mechanisms of resistance to therapy is warranted to bridge this unmet need. Here, we make use of genome-wide CRISPR-Cas9 knockout screens in SMB21 and DAOY cells, in order to unravel genetic dependencies and drug-related genetic interactors that could serve as alternative therapeutic targets for SHH-MB. Our screens reinforce SMB21 cells as a faithful model system for SHH-MB, as opposed to DAOY cells, and identify members of the epigenetic machinery including DNA methyltransferase 1 (DNMT1) as druggable targets in SHH-dependent tumors. We show that Dnmt1 plays a crucial role in normal murine cerebellar development and is required for SHH-MB growth in vivo. Additionally, DNMT1 pharmacological inhibition alone and in combination with SMO inhibition effectively inhibits tumor growth in murine and human SHH-MB cell models and prolongs survival of SHH-MB mouse models by inhibiting SHH signaling output downstream of SMO. In conclusion, our data highlight the potential of inhibiting epigenetic regulators as a novel therapeutic avenue in SMO-inhibitor sensitive as well as resistant SHH-MBs.

2024-06-13 | GSE269265 | GEO

Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma [RNA-seq]

2024-06-13 | GSE269462 | GEO

Sonic Hedgehog subgroup medulloblastomas

Project description:Sonic Hedgehog subgroup medulloblastomas

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Sonic Hedgehog inhibitor cyclopamine effect on JAR cells

Project description:Physiologically, trophoblast progenitor cells differentiate into placental villous cytotrophoblast cells (CTBs). CTBs either differentiate into invasive lineage to yields extravillous cytotrophoblast cells (EVTs), or undergo cell fusion lineage to yields syncytiotrophoblast cells (STBs)，Sonic hedgehog (Shh) together with indian hedgehog (Ihh) and desert hedgehog (Dhh) consist of ligand of hedgehog signaling pathway, which plays pivotal roles in regulating cell proliferation, cell differentiation, organogenesis and development, even involving in tumorigenesis and progression. previous study had summarized and indicatedthat hedgehog proteins played important roles in regulating hematopoiesis, vasculogenesis and angiogenesis during embryogenesis and development. Herein, we investigate the effect of the Sonic Hedgehog morphogen inhibitor Cyclopamine on JAR cells

2019-12-31 | GSE130367 | GEO

A Druggable UHRF1/DNMT1/GLI Complex Regulates Sonic Hedgehog-Dependent Tumor Growth.

Project description:Dysregulation of Sonic hedgehog (SHH) signaling drives the growth of distinct cancer subtypes, including medulloblastoma (MB). Such cancers have been treated in the clinic with a number of clinically relevant SHH inhibitors, the majority of which target the upstream SHH regulator, Smoothened (SMO). Despite considerable efficacy, many of these patients develop resistance to these drugs, primarily due to mutations in SMO. Therefore, it is essential to identify druggable, signaling components downstream of SMO to target in SMO inhibitor resistant cancers. We utilized an integrated functional genomics approach to identify epigenetic regulators of SHH signaling and identified a novel complex of Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), DNA methyltransferase 1 (DNMT1), and GLI proteins. We show that this complex is distinct from previously described UHRF1/DNMT1 complexes, suggesting that it works in concert to regulate GLI activity in SHH driven tumors. Importantly, we show that UHRF1/DNMT1/GLI complex stability is targeted by a repurposed FDA-approved therapy, with a subsequent reduction in the growth of SHH-dependent MB ex vivo and in vivo.ImplicationsThis work describes a novel, druggable UHRF1/DNMT1/GLI complex that regulates SHH-dependent tumor growth, and highlights an FDA-approved drug capable of disrupting this complex to attenuate tumor growth.

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Sonic hedgehog Activation Restores Interneurons and Cognitive Function in Newborns with Intraventricular Hemorrhage

Project description:We hypothesized that the occurrence of IVH would reduce interneuron neurogenesis in the medial ganglionic eminence and diminish the population of parvalbumin+ and somatostatin+ cortical interneurons. Since Sonic Hedgehog promotes the production of cortical interneurons, we also postulated that the activation of Sonic Hedgehog signaling might restore neurogenesis, cortical interneuron population, and neurobehavioral function in premature newborns with IVH.

2022-08-06 | GSE210477 | GEO

Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model

Project description:The causative role of activated Hedgehog signaling in liver fibrosis was investigated in vivo. Using hydrodynamics-based transfection, a transgenic mouse model has been developed that expresses Sonic Hedgehog (SHH), a ligand for Hedgehog signaling, in the liver. Levels of hepatic fibrosis and fibrosis-related gene expression were assessed in the model.

2015-10-30 | E-GEOD-72758 | biostudies-arrayexpress

Transcriptional responses to Sonic Hedgehog pathway stimulation in in vitro derived neural progenitors

Project description:The objective of this study was to identify genes regulated by Sonic Hedgehog pathway stimulation in neural progenitors.

2012-12-15 | GSE42565 | GEO