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

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

PROVIDER: PRJNA601229 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10894625_1.fastq.gz	Fastqsanger.gz
	SRR10894625_2.fastq.gz	Fastqsanger.gz
	SRR10894626_1.fastq.gz	Fastqsanger.gz
	SRR10894626_2.fastq.gz	Fastqsanger.gz
	SRR10894627_1.fastq.gz	Fastqsanger.gz

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

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.

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Gene expression in response to knockdown of GLI1.

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

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Selective PROTAC-mediated degradation and shRNA-driven knockdown of SMARCA2 in HCC2302 lung adenocarcinoma cells

Project description:SMARCA2 and SMARCA4 are mutually-exclusive, core catalytic subunits for the chromatin remodeling SWI/SNF complex. Mutations in SMARCA4 are common in lung adenocarcinoma and have shown synthetic lethality with loss of SMARCA2 loss of function. The purpose of this project is to answer questions related to the in vivo [mouse xenograft] efficacy of A947, a SMARCA2 degrader. The study involves in vitro versus in vivo comparisons of drug activity, in addition to genetic manipulation of the target. Model system: HCC2302 (RRID:CVCL_V636); Model origin: Lung Adenocarcinoma; Perturbation: A947 (VHL-PROTAC-based degrader)

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Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers

Project description:The mammalian SWI/SNF helicase SMARCA4 is frequently mutated in cancer and inactivation results in a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving a high degree of SMARCA2 selectivity is likely essential to afford an acceptable therapeutic index and this has been a considerable challenge due to the homology between paralogs. Herein we report the discovery of the first potent and selective SMARCA2 proteolysis-targeting chimera (PROTAC) molecule. Selective degradation was achieved in the absence of selective PROTAC binding and translated to potent in vitro growth inhibition and in vivo efficacy in SMARCA4 mutant models, compared to wild type models. Global ubiquitin mapping and proteome profiling revealed no unexpected off-target degradation. Our study thus highlights the ability to transform a non-selective SMARCA2-binding ligand into a selective and efficacious in vivo SMARCA2 PROTAC, providing a potential therapeutic opportunity for SMARCA4 mutant patients.

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Project description:Mammalian SWI/SNF complexes are multi-subunit chromatin remodeling complexes associated with an ATPase, either SMARCA4 or SMARCA2. Heterozygous mutations in the SMARCA2 ATPase cause Nicolaides-Baraitser Syndrome (NCBRS), an intellectual disability syndrome associated with delayed speech onset. We engineered human embryonic stem cells (hESCs) to carry NCBRS-associated heterozygous SMARCA2 K755R or R1159Q mutations. While SMARCA2 mutant hESCs were phenotypically normal, differentiation to neural progenitors cells (NPCs) was severely impaired. We find that SMARCA2 mutations cause enhancer reorganization with loss of SOX3-dependent neural enhancers and prominent emergence of astrocyte-specific de novo enhancers. Changes in chromatin accessibility at enhancers were associated with an increase in SMARCA2 binding and retargeting of SMARCA4. We show that AP-1 family member FRA2 is aberrantly overexpressed in SMARCA2 mutant NPCs, where it functions as a pioneer factor at de novo enhancers. Together, our results demonstrate SMARCA2 mutations cause impaired differentiation through enhancer reprogramming via inappropriate targeting of SMARCA4.

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