SMARCA4 regulates spatially restricted metabolic plasticity in 3D multicellular tissue

Abstract SWI/SNF and related chromatin remodeling complexes act as tissue-specific tumor suppressors and are frequently inactivated in different cancers. Although many regulatory activities of SWI/SNF have been identified using 2D cell culture, the effects of SWI/SNF alterations in more complex 3D t...

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Published inbioRxiv
Main Authors Cermakova, Katerina, Smith, Eric A, Yuen San Chan, Mario Loeza Cabrera, Chambers, Courtney, Jarvis, Maria I, Simon, Lukas M, Xu, Yuan, Jain, Abhinav, Putluri, Nagireddy, Chen, Rui, R Taylor Ripley, Veiseh, Omid, H Courtney Hodges
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 22.03.2021
Subjects
Activating transcription factor 3
Activator protein 1
Adenocarcinoma
Adenosine triphosphatase
Antioxidants
BRG1 protein
Cell culture
Cell death
Chromatin remodeling
Deoxyribonucleic acid
Derepression
DNA
Ferroptosis
Gene expression
Metabolism
Spheroids
Transcription factors
Transcriptomics
Tumors
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Summary:Abstract SWI/SNF and related chromatin remodeling complexes act as tissue-specific tumor suppressors and are frequently inactivated in different cancers. Although many regulatory activities of SWI/SNF have been identified using 2D cell culture, the effects of SWI/SNF alterations in more complex 3D tissues have remained poorly understood. Here we employed 3D cell culture conditions that yield transcriptomic states mirroring primary lung adenocarcinoma (LUAD) specimens better than 2D culture. By analyzing spatial patterns of gene expression and DNA accessibility in 3D spheroids using single-cell RNA-seq and ATAC-seq, we find that the SWI/SNF ATPase SMARCA4 (BRG1) induces state-specific changes to DNA accessibility that influence spatially heterogeneous expression patterns and metabolism. In 3D conditions, SMARCA4 promotes accessibility for AP-1 transcription factors, including ATF3, a regulator of metabolism and repressor of NRF2 antioxidant signaling. These changes reduce expression of SLC7A11 in a distinct portion of cells, which sensitizes A549 spheroids to cell death via ferroptosis under oxidizing conditions. Consistent with these results, we find that SMARCA4 alterations are associated with derepression of NRF2 targets in human tumors independently of NRF2/KEAP1 status. Our work reveals new 3D-specific features and unanticipated spatial complexity associated with chromatin remodeling in multicellular tissues. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2021.03.21.436346