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Chromatin accessibility in response to knockdown of GLI1 and SMARCA2 in GLI1-mediated gene expression.

ABSTRACT: GLI1 is a transcription factor correlated to decreased survival in several cancers. We have identified SMARCA2 as a co-regulator that enhances GLI1-mediated transcriptional activity and functions through the C-terminal transcriptional activation domain of GLI1. Central domains including the ATPase motif of SMARCA2 physically interact with GLI1. Evaluation of DNA density indicates GLI1, like SMARCA2, can increase the DNA accessibility with a preference for sites distal to gene transcription start sites and outside the promoter regions (i.e. enhancers). The putative enhancers where accessibility is decreased by the knock down of GLI1 and SMARCA2 are located cis to genes, such as HHIP, that are regulated by GLI1 and implicated in cancer functions. At the putative enhancer for HHIP, the localization of SMARCA2 is at least partially dependent on GLI1’s presence. Understanding this transcriptional regulation by GLI1 and SMARCA2 through altering chromatin accessibility at enhances can provide additional therapeutic targets for cancers dependent on GLI1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143684 | GEO | 2020/05/11

REPOSITORIES: GEO

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Gene expression in response to knockdown of GLI1.

Project description:GLI1 is a transcription factor correlated to decreased survival in several cancers. We have identified SMARCA2 as a co-regulator that enhances GLI1-mediated transcriptional activity and functions through the C-terminal transcriptional activation domain of GLI1. Central domains including the ATPase motif of SMARCA2 physically interact with GLI1. Evaluation of DNA density indicates GLI1, like SMARCA2, can increase the DNA accessibility with a preference for sites distal to gene transcription start sites and outside the promoter regions (i.e. enhancers). The putative enhancers where accessibility is decreased by the knock down of GLI1 and SMARCA2 are located cis to genes, such as HHIP, that are regulated by GLI1 and implicated in cancer functions. At the putative enhancer for HHIP, the localization of SMARCA2 is at least partially dependent on GLI1’s presence. Understanding this transcriptional regulation by GLI1 and SMARCA2 through altering chromatin accessibility at enhances can provide additional therapeutic targets for cancers dependent on GLI1.

2020-05-11 | GSE143681 | GEO

Chromatin accessibility in response to knockdown of GLI1 and SMARCA2 in GLI1-mediated gene expression.

Project description:Chromatin accessibility in response to knockdown of GLI1 and SMARCA2 in GLI1-mediated gene expression.

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Heterozygous mutations in SMARCA2 lead to impaired neurogenesis due to global retargeting of SMARCA4

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2019-07-30 | GSE122631 | GEO

Chromatin accessibility of lung cancer cells reconstituted with SMARCA4 WT or SMARCA4 mutants with and without SMARCA2 depletion

Project description:Using ATAC-seq, we identified the accessibility changes in lung cancer cells (NCI-H1944) reconstituted with SMARCA4 WT or SMARCA4 mutants. We also determined the SMARCA2-regulated accessibility program in NCI-H1944 after SMARCA2 depletion. Lastly, we identified the SMARCA2 accessibility program that is rescued by SMARCA4 WT and mutants. The "SAMPLE_ID" sample characteristic is a sample identifier internal to Genentech.

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Expression data from GLI1-transformed RK3E cells

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Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to generate medulloblastoma-initiating cells

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2019-12-12 | GSE100936 | GEO

Genome binding of SMARCA2 and SMARCA4 in lung cancer cells reconstituted with SMARCA4 WT with and without SMARCA2 depletion

Project description:Using ChIP-seq, we identified the genome-wide occupancy of SMARCA2 and SMARCA4 in lung cancer cells (NCI-H1944) reconstituted with SMARCA4 WT. We also determined how SMARCA4 occupancy changed in NCI-H1944 after SMARCA2 depletion.

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Transcriptomic analysis of loss of Gli1 in neural stem cells responding to demyelination in the mouse brain.

Project description:In the adult mammalian brain, Gli1 expressing neural stem cells reside in the subventricular zone and their progeny are recruited to sites of demyelination in the white matter where they regenerate oligodendrocytes, the myelin forming cells. Remarkably, genetic and pharmacologic inhibition of Gli1 enhances remyelination in the adult brain. To understand the molecular mechanisms involved, we performed a transcriptomic analysis to compare the expression of genes in Gli1 neural stem cells with either intact Gli1 expression or genetic loss of Gli1 from adult mice on control diet or cuprizone diet, which induces demyelination. These data will be a valuable resource for identifying therapeutic targets for enhancing remyelination in demyelinating diseases like multiple sclerosis.

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A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

Project description:Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit the target and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. The oral route of administration is the option of choice in the clinic, but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4 deficient cancers. Here we outline structure- and property-guided approaches that led to the first orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.

2022-06-20 | PXD032239 | Pride

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