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Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [RNA-seq]

ABSTRACT: Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [RNA-seq]

PROVIDER: PRJNA753533 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15410454.fastq.gz	Fastqsanger.gz
	SRR15410455.fastq.gz	Fastqsanger.gz
	SRR15410456.fastq.gz	Fastqsanger.gz
	SRR15410457.fastq.gz	Fastqsanger.gz
	SRR15410458.fastq.gz	Fastqsanger.gz

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Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CUT&TAG]

Project description:Precise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and is frequently corrupted in cancer. By coupling a cell surface readout of bivalent MHC class I gene expression with whole genome CRISPR/Cas9 screens, we identify specific roles for MTF2-PRC2.1, PCGF1-PRC1.1 and Menin- KMT2A/B complexes in maintaining bivalency. Unexpectedly, genetic loss or pharmacological inhibition of Menin phenocopies the effects of polycomb disruption, resulting in derepression of bivalent genes in both cancer cells and pluripotent stem cells. Whilst Menin and KMT2A/B contribute to H3K4me3 at active genes, a separate Menin-independent function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent genes. Release of KMT2A from active genes following Menin targeting alters the balance of polycomb and KMT2A at bivalent genes, facilitating gene activation. This functional partitioning of Menin-KMT2A/B complex components reveals novel therapeutic opportunities that can be leveraged through inhibition of Menin.

2023-01-13 | GSE222516 | GEO

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes

Project description:Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes

| PRJNA753530 | ENA

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CRISPR]

Project description:Precise dynamic control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent gene promoters is essential for normal development and frequently corrupted in cancer. Using whole genome CRISPR/Cas9 screens we identify specific roles for MTF2-PRC2.1 and PCGF1-PRC1.1 polycomb complexes, and MLL1/2-COMPASS-like complex components in maintaining bivalency. Contrary to expectations, loss of Menin or inhibition of the Menin-MLL1/2 interaction, induces activation of bivalent genes via loss of polycomb-mediated repression and defines distinct roles for MLL1/2 and Menin in gene regulation. Whilst Menin and MLL1/2 contribute to maintenance H3K4me3 at active genes, a separate Menin-independent function of MLL1/2 opposes polycomb mediated repression at bivalent genes. MLL1/2 are essential for basal transcription and, although dispensable for transcription factor driven activation, facilitate transcriptional consistency during dynamic changes in gene expression. This functional partitioning of COMPASS complex components reveals therapeutic opportunities to target oncogenic and immunosuppressive functions of PRC2 through pharmacological inhibition of Menin.

2023-01-13 | GSE181818 | GEO

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [RNA-seq]

2023-01-13 | GSE181828 | GEO

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [ChIP-seq]

2023-01-13 | GSE181823 | GEO

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CRISPR]

Project description:Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CRISPR]

| PRJNA753522 | ENA

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CUT&TAG]

Project description:Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CUT&TAG]

| PRJNA922457 | ENA

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [ChIP-seq]

Project description:Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [ChIP-seq]

| PRJNA753529 | ENA

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes.

Project description:Precise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and frequently corrupted in cancer. By coupling a cell surface readout of bivalent MHC class I gene expression with whole-genome CRISPR-Cas9 screens, we identify specific roles for MTF2-PRC2.1, PCGF1-PRC1.1 and Menin-KMT2A/B complexes in maintaining bivalency. Genetic loss or pharmacological inhibition of Menin unexpectedly phenocopies the effects of polycomb disruption, resulting in derepression of bivalent genes in both cancer cells and pluripotent stem cells. While Menin and KMT2A/B contribute to H3K4me3 at active genes, a separate Menin-independent function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent genes. Release of KMT2A from active genes following Menin targeting alters the balance of polycomb and KMT2A at bivalent genes, facilitating gene activation. This functional partitioning of Menin-KMT2A/B complex components reveals therapeutic opportunities that can be leveraged through inhibition of Menin.

| S-EPMC7614190 | biostudies-literature

UBR5 Mediates Menin Inhibitor Dependent Menin/KMT2A Complex Stability [ChIP-seq]

Project description:The chromatin adaptor protein Menin (MEN1) is required by acute leukemias driven by mixed lineage leukemia 1 gene rearrangements (KMT2A-r) for sustained leukemogenesis. Menin inhibitors (MIs), which disrupt the Menin-KMT2A interface leading to downregulation of Menin-KMT2A oncogenic transcriptional programs, have shown promising results in recent clinical trials treating acute myeloid leukemia (AML). Decreased Menin protein stability has been observed following treatment with several MIs though proteasomal degradation, though the biological mechanisms that control Menin stability are not well understood. Here we interrogate and compare five clinical MIs and two pre-clinical compounds to characterize the mechanism by which MIs induce Menin degradation and demonstrate that the loss of the Menin-KMT2A interaction results in decreased protein stability of Menin and KMT2A. We have identified the HECT E3 ubiquitin ligase UBR5 as a regulator of Menin protein stability and demonstrate that UBR5 binds to similar sites as the Menin/KMT2A complex on chromatin. Loss of UBR5 leads to transcriptional rescue of Menin-KMT2A target genes leading to decreased sensitivity to all MIs. Thus, we present UBR5 as an important regulator of Menin/KMT2A complex stability and Menin destabilization/subcellular localization as a designable feature of Menin inhibition targeting KMT2A-r leukemias.

2025-08-01 | GSE299100 | GEO

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