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MOZ and Menin-MLL Complexes are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor [RNA-seq]

ABSTRACT: MOZ and Menin-MLL Complexes are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor [RNA-seq]

PROVIDER: PRJNA722253 | ENA |

REPOSITORIES: ENA

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MOZ and Menin-MLL Complexes are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor [RNA-seq]

Project description:Gastrointestinal stromal tumor (GIST) is commonly characterized by activating mutations in the receptor tyrosine kinase KIT. Tyrosine kinase inhibitors are the only approved therapy for GIST, and other complementary treatment strategies are urgently needed. As GIST both lacks oncogene amplification and relies upon an established network of transcription factors, we hypothesized that unique chromatin modifying enzymes are essential in orchestrating the GIST epigenome. Here, we identified through genome-wide CRISPR screening that MOZ and Menin-MLL chromatin regulatory complexes are cooperative and unique dependencies in GIST. These complexes were enriched at GIST-relevant genes and regulated their transcription. Inhibition of MOZ and Menin-MLL complexes decreased GIST cell proliferation by disrupting interactions with transcriptional regulators, such as DOT1L. Menin inhibition caused significant reductions in tumor burden in xenograft models, with superior effects observed in combination with imatinib. These results define unique chromatin regulatory dependencies in GIST and identify therapeutic strategies for clinical application.

2022-05-02 | GSE172153 | GEO

MOZ and Menin-MLL Complexes are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor [ChIP-seq and CUT&Tag]

2022-05-02 | GSE172152 | GEO

MOZ and Menin-MLL Complexes are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor

Project description:MOZ and Menin-MLL Complexes are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor

| PRJNA722244 | ENA

MOZ and Menin-MLL Complexes are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor [ChIP-seq and CUT&Tag]

Project description:MOZ and Menin-MLL Complexes are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor [ChIP-seq and CUT&Tag]

| PRJNA722252 | ENA

MOZ and Menin-MLL Complexes are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor

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

2022-05-02 | GSE172154 | GEO

The genome wide mapping of H3K9 and H3K23 acetylation in Moz+/+ and Moz-/- MOZ-TIF2 AML cells

Project description:Monocytic leukemia Zinc finger protein (MOZ) is a MYST-type acetyltransferase involved in chromosomal translocation in acute myelogenous leukemia (AML) and myelodysplastic syndrome. MOZ is established as essential for hematopoiesis; however, the role of MOZ in AML has not been addressed. We propose that MOZ is critical for AML development induced by MOZ-TIF2 fusions. Moz-deficient hematopoietic stem/progenitor cells (HSPCs) expressing MOZ-TIF2 could form colonies in vitro but could not induce AML in mice. By contrast, Moz was dispensable for colony formation by HOXA9-transduced cells and AML development caused by HOXA9 and MEIS1, suggesting a specific requirement for MOZ in AML induced by MOZ/MLL-fusions. Expression of the of Meis1, but not Hoxa9, was reduced in Moz-deficient MOZ-TIF2 AML cells. AML development induced by MOZ-TIF2 was rescued by introducing Meis1 into Moz-deficient cells carrying MOZ-TIF2. Meis1 deletion impaired MOZ-TIF2-mediated AML development. Active histone modifications were also severely reduced at the Meis1 locus in Moz-deficient MOZ-TIF2 AML cells. These results suggest that endogenous MOZ is critical for MOZ-fusion-induced AML development and maintains active chromatin signatures at target gene loci.

2022-07-24 | GSE208741 | GEO

Comparision of Psip1/p75, Mll and Menin binding on the Hox and non-Hox genes

Project description:Menin binding pattern in WT and Psip1 KO MEFs Menin occupancy is studied over Hox genes Menin ChIP from WT and Psip1 KO MEFs ChIP-chip

2014-06-27 | E-GEOD-49180 | biostudies-arrayexpress

A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition [RNA-seq]

Project description:The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded by MLL1-rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. Here, we delineate a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that Menin safeguards leukemia cell fitness by impeding binding of the histone demethylase UTX at a subset of non-canonical target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of genes with tumor suppressive function. We show that this epigenetic mechanism is operative in murine and human models of AML, and clinical responses to Menin-MLL inhibition in primary human leukemia are accompanied by induction of tumor suppressive gene expression at Menin-UTX targets. These findings shed light on the context-dependent and often antagonistic roles that chromatin regulators exhibit in development and disease and provide mechanistic insight for rational design of targeted epigenetic therapies.

2022-11-16 | GSE186709 | GEO

A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition [ChIP-seq]

2022-11-16 | GSE186695 | GEO

Effect of Menin cKO on MLL-AF9 transformed cells

Project description:We determined the effect of conditional deletion of Menin in MLL-AF9 transformed leukemia cells

2018-08-01 | GSE117933 | GEO