GEO series
Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [ATAC-Seq]
GSE236588
Homo sapiens (human)
ChIP-seq / ATAC-seq (genome binding and open chromatin)
24 samples
Submitted 2024/09/27
Platform GPL24676
At a glance
ChIP-seq / ATAC-seq (genome binding and open chromatin) · human · 24 samples
- What it is
- ChIP-seq / ATAC-seq (genome binding and open chromatin)Where proteins bind the genome, or which regions are open and active.
- Organism
- Homo sapiens (human)
- Samples
- 24 samples: 12 conditions, mostly in duplicateGroups are read from the sample names, not from the paper. Check the list below.
- Data you can get
- A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
- Paper
- Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancerCell chemical biology · 2024
Summary (written by the submitters)
Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer still lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer.
Read the full summary ↓
Recent reports have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. To overcome this hurdle, we have utilized iterative structure-activity relationship (SAR) studies to develop novel, potent and selective SMARCA2 degrading small molecules based on proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. Mechanistically, we show that SMARCA2 degradation in SMARCA4-mutant cells induces a profound reprograming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified nuclear effectors of the Hippo pathway, YAP/TEAD, as key co-conspirators of SMARCA2 in driving the growth of SMARCA4-mutant cancer cells that can be disrupted by our degrader. Finally, we show that YD23 has a potent tumor growth inhibitory activity in SMARCA4-mutant xenograft tumors. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4 mutant tumors.
Published in
Kotagiri S, Blazanin N, Xi Y et al.
· Cell chemical biology 2024
· PMID 39378885
· doi:10.1016/j.chembiol.2024.09.004
This dataset
Download · which file do I need?
Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.
1 · Just have a look
Processed table
The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.
2 · Re-analyse it
Supplementary files
The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE236588_RAW.tar (it can run to tens of gigabytes).
3 · Start from the raw reads
Raw sequencing reads
The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.
What the files usually look like: Look for peak files (.bed, .narrowPeak) and signal tracks (.bigWig) among the supplementary files; the raw reads are on ENA.
Also filed as BioProject PRJNA991607 and SRA study SRP447543. Searching any of these in the dataset finder brings you back here.
Study design
12 conditions, mostly in duplicate
[ATAC-Seq] H1693, ACBi1, ×2
[ATAC-Seq] H1693, DMSO, ×2
[ATAC-Seq] H1693, YD23, ×2
[ATAC-Seq] H1975, ACBi1, ×2
[ATAC-Seq] H1975, DMSO, ×2
[ATAC-Seq] H1975, YD23, ×2
[ATAC-Seq] H322, ACBi1, ×2
[ATAC-Seq] H322, DMSO, ×2
+4 more
Supports a between-group comparison across 24 samples.
How we read this: 12 replicated groups read from 24 sample titles; they account for 24 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.
Samples in this study
- GSM7559405 [ATAC-Seq] H1693, ACBi1, replicate 1 [ATAC-Seq] H1693, ACBi1,
- GSM7559406 [ATAC-Seq] H1693, DMSO, replicate 1 [ATAC-Seq] H1693, DMSO,
- GSM7559407 [ATAC-Seq] H1693, YD23, replicate 1 [ATAC-Seq] H1693, YD23,
- GSM7559408 [ATAC-Seq] H1975, ACBi1, replicate 1 [ATAC-Seq] H1975, ACBi1,
- GSM7559409 [ATAC-Seq] H1975, DMSO, replicate 1 [ATAC-Seq] H1975, DMSO,
- GSM7559410 [ATAC-Seq] H1975, YD23, replicate 1 [ATAC-Seq] H1975, YD23,
- GSM7559411 [ATAC-Seq] H322, ACBi1, replicate 1 [ATAC-Seq] H322, ACBi1,
- GSM7559412 [ATAC-Seq] H322, DMSO, replicate 1 [ATAC-Seq] H322, DMSO,
- GSM7559413 [ATAC-Seq] H322, YD23, replicate 1 [ATAC-Seq] H322, YD23,
- GSM7559414 [ATAC-Seq] HCC44, ACBi1, replicate 1 [ATAC-Seq] HCC44, ACBi1,
- GSM7559415 [ATAC-Seq] HCC44, DMSO, replicate 1 [ATAC-Seq] HCC44, DMSO,
- GSM7559416 [ATAC-Seq] HCC44, YD23, replicate 1 [ATAC-Seq] HCC44, YD23,
- GSM7559417 [ATAC-Seq] H1693, ACBi1, replicate 2 [ATAC-Seq] H1693, ACBi1,
- GSM7559418 [ATAC-Seq] H1693, DMSO, replicate 2 [ATAC-Seq] H1693, DMSO,
- GSM7559419 [ATAC-Seq] H1693, YD23, replicate 2 [ATAC-Seq] H1693, YD23,
- GSM7559420 [ATAC-Seq] H1975, ACBi1, replicate 2 [ATAC-Seq] H1975, ACBi1,
- GSM7559421 [ATAC-Seq] H1975, DMSO, replicate 2 [ATAC-Seq] H1975, DMSO,
- GSM7559422 [ATAC-Seq] H1975, YD23, replicate 2 [ATAC-Seq] H1975, YD23,
- GSM7559423 [ATAC-Seq] H322, ACBi1, replicate 2 [ATAC-Seq] H322, ACBi1,
- GSM7559424 [ATAC-Seq] H322, DMSO, replicate 2 [ATAC-Seq] H322, DMSO,
- GSM7559425 [ATAC-Seq] H322, YD23, replicate 2 [ATAC-Seq] H322, YD23,
- GSM7559426 [ATAC-Seq] HCC44, ACBi1, replicate 2 [ATAC-Seq] HCC44, ACBi1,
- GSM7559427 [ATAC-Seq] HCC44, DMSO, replicate 2 [ATAC-Seq] HCC44, DMSO,
- GSM7559428 [ATAC-Seq] HCC44, YD23, replicate 2 [ATAC-Seq] HCC44, YD23,
Datasets on a similar topic
- GSE236589 Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [ChIP-Seq] 12 samples shares smarca2, smarca4, reprogramming, therapeutic, underlies, enhancer, degrader
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- GSE305637 Transcriptomic Reprogramming of T Cells Underlies Rituximab Efficacy in Idiopathic Nephrotic Syndrome 24 samples shares reprogramming, underlies
- GSE286923 Modularity of OCT4 underlies its functional diversity in reprogramming and embryonic development. 19 samples shares reprogramming, underlies
- GSE292538 KRAS-Dependent Metabolic Reprogramming of Endothelial Cells as a Therapeutic Vulnerability in Brain Arteriovenous Malformations 18 samples shares reprogramming, therapeutic
- GSE307259 c-JUN Enhances CRISPR Knock-In anti-B7-H3 CAR T-cell Function for Treatment of Small Cell Lung Cancer and thoracic SMARCA4-deficient undifferentiated tumors 12 samples shares smarca4
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