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Non-Canonical BAF and mSWI/SNF Regulates POU2F3 and are Selective Targetable Dependencies for POU2F3-Positive Small Cell Lung Cancer

GSE249362 Homo sapiens (human) ChIP-seq / ATAC-seq (genome binding and open chromatin) 125 samples Submitted 2024/06/14 Platform GPL18573Platform GPL24676
At a glance

ChIP-seq / ATAC-seq (genome binding and open chromatin) · human · 125 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)
Topic
Small cell lung cancerThis series is part of our curated briefing on it.
Samples
125 samples: 125 samples, each with a distinct title — no replicated groupsGroups 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
Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancerCancer cell · 2024
Summary (written by the submitters)
~12% of SCLCs are marked by the lineage transcription factor POU2F3, which is essential in all POU2F3-positive SCLCs. Thus, approaches to directly or indirectly inhibit POU2F3 could lead to new therapeutic strategies for POU2F3-positive SCLCs. Here we use a positive selection screening strategy where endogenous POU2F3 is fused to the suicide gene DCK*.
Read the full summary ↓
Cells that express endogenous POU2F3-DCK* are killed in the presence of the nucleoside analog BVdU and only cells that downregulate the POU2F3-DCK* fusion survive. Genome-wide CRISPR/Cas9 resistance screens with BVdU in POU2F3-DCK* cells uncovered that inactivation of SMARCD1 or BRD9, both components of the non-canonical BAF (ncBAF) complex, markedly downregulate endogenous POU2F3. We find that all POU2F3-positive SCLC cell lines relative to ASCL1-positive and NEUROD1-positive cell lines, are exquisitely sensitive to mSWI/SNF complex inhibition using SMARCA2/4 inhibitors; while pure non-neuroendocrine POU2F3-positive SCLC cell lines are highly sensitive to ncBAF complex inhibition using highly selective BRD9 degraders. Mechanistically, BRD9 binds and regulates POU2F3 target genes including POU2F3 itself. BRD9 degraders or SMARCA2/4 inhibitors robustly decrease accessibility of POU2F3 target genes effectively shutting off POU2F3 function. Moreover, BRD9 degraders or SMARCA2/4 inhibitors decrease tumor growth and increase survival of mice bearing non-neuroendocrine POU2F3 xenografts. This works shows that mSWI/SNF and ncBAF tightly regulate POU2F3 expression and activity and nominate mSWI/SNF or ncBAF inhibition as druggable therapeutic strategies to selectively target POU2F3-positive SCLCs.
Published in
Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer
Duplaquet L, So K, Ying AW et al. · Cancer cell 2024 · PMID 39029464 · doi:10.1016/j.ccell.2024.06.012
This dataset
Open GSE249362 in finder → Find more human RNA-seq datasets → Small cell lung cancer landscape →
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.

Series matrix ↓
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 GSE249362_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
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.

Raw reads on ENA ↗

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 PRJNA1048875 and SRA study SRP476060. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 39029464) ↗
Study design
125 samples, each with a distinct title — no replicated groups

Any grouping that defines a comparison lives in the sample characteristics, which GEO records separately from the titles.

How we read this: Read from 125 sample titles: 125 distinct titles with little repetition. 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

+ 85 more — browse all 125 samples with per-sample file links →

More Small cell lung cancer datasets

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