BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Panditharatna, Eshini; Marques, Joana G.; Wang, Tingjian; Trissal, Maria; Liu, Ilon; Jiang, Li; Beck, Alexander; Groves, Andrew; Dharia, Neekesh V.; Li, Deyao; Hoffman, Samantha E.; Kugener, Guillaume; Shaw, McKenzie; Mire, Hafsa M.; Hack, Olivia A.; Dempster, Joshua M.; Lareau, Caleb A.; Dai, Lingling; Sigua, Logan H.; Quezada, Michael A.; Stanton, Ann-Catherine J.; Wyatt, Meghan; Kalani, Zohra; Goodale, Amy; Vázquez, Francisca; Piccioni, Federica; Doench, John G.; Root, David E.; Anastas, Jamie N.; Jones, Kristen L.; Conway, Amy Saur; Stopka, Sylwia A.; Regan, Michael S.; Liang, Yu; Seo, Hyuk-Soo; Song, Kijun; Bashyal, Puspalata; Jerome, William P.; Mathewson, Nathan D.; Dhe‐Paganon, Sirano; Suvà, Mario L.; Carcaboso, Ángel M.; Lavarino, Cinzia; Mora, Jaume; Nguyen, Quang-Dé; Ligon, Keith L.; Shi, Yang; Agnihotri, Sameer; Agar, Nathalie Y.R.; Stegmaier, Kimberly; Stiles, Charles D.; Monje, Michelle; Golub, Todd R.; Qi, Jun; Filbin, Mariella G.

doi:10.1158/2159-8290.cd-21-1491

Cited by 17 publications

(15 citation statements)

References 84 publications

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“…BRD9 is a component of the non-canonical BAF chromatin remodelling complex (ncBAF) 35 and has recently been shown to constitute a barrier in reprogramming of somatic cells to induced pluripotent stem cells 36 . The catalytic component SMARCA4 of the BAF complex regulates stem cell properties in pediatric gliomas and provides a possible therapeutic angle in glioblastoma treatment 37 . Collectively these data provided evidence to focus our investigation on the molecular role of the BAF complex and BRD9 in particular, in PDAC CSCs.…”

Section: Resultsmentioning

confidence: 99%

BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma

Feng

Cai

Pook

et al. 2023

Preprint

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The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodelling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signalling pathway. Inhibition and genetic ablation of BDR9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumours from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

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Section: Resultsmentioning

confidence: 99%

BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma

Feng

Cai

Pook

et al. 2023

Preprint

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“…These include oncogenic fusion of the BAF subunit SS18 with an SSX protein in synovial sarcoma and interaction of BAF with EWS-FLI1 in Ewing sarcoma causing aberrant BAF complex targeting 74,75 , subunit overexpression 76 , and heterozygous missense mutations within the Brg1 subunit gene in diverse cancers, several of which were characterized as gain-offunction for remodeling activity 77 . Furthermore, genetic dependency on Brg1 observed in several cancers has led to the emergence of pharmacological inhibition of the BRG1 ATPase activity as a novel therapeutic strategy [78][79][80] . Our study explains how BAF can synergize with cell-typespecific chromatin regulators and TFs, shedding light into how BAF functions may be hijacked in cancers.…”

Section: Discussionmentioning

confidence: 99%

RNA Polymerase II, the BAF remodeler and transcription factors synergize to evict nucleosomes

Brahma

Henikoff

2023

Preprint

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Chromatin accessibility is a hallmark of active transcription and requires ATP-dependent nucleosome remodeling by Brahma-Associated Factor (BAF). However, the mechanistic link between transcription, nucleosome remodeling, and chromatin accessibility is unclear. Here, we used a chemical-genetic approach to dissect the interplay between RNA Polymerase II (RNAPII), BAF, and DNA-sequence-specific transcription factors (TFs) in mouse embryonic stem cells. By time-resolved chromatin profiling with acute transcription block at distinct stages, we show that RNAPII promoter-proximal pausing stabilizes BAF chromatin occupancy and enhances nucleosome eviction by BAF. We find that RNAPII and BAF probe both transcriptionally active and Polycomb-repressed genomic regions and provide evidence that TFs capture transient site exposure due to nucleosome unwrapping by BAF to confer locus specificity for persistent chromatin remodeling. Our study reveals the mechanistic basis of cell-type-specific chromatin accessibility. We propose a new paradigm for how functional synergy between dynamically acting chromatin factors regulates nucleosome organization.

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“…H3C1 is a member of histone family ( 30 ). Missense mutations in histone related genes promote tumor progression, a process known as oncohistones, which is a major challenge for tumor treatment ( 31 , 32 ). Yi.H et al revealed for the first time that high expression of histone deacetylase 7 (HDAC7) was closely associated with poor in EC, suggesting that HDAC7 is a potential cancer-promoting agent ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Prognostic model construction and validation of esophageal cancer cellular senescence-related genes and correlation with immune infiltration

Zheng

Lin²,

Wu³

et al. 2023

Front. Surg.

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IntroductionCellular senescence is a cellular response to stress, including the activation of oncogenes, and is characterized by irreversible proliferation arrest. Restricted studies have provided a relationship between cellular senescence and immunotherapy for esophageal cancer.MethodsIn the present study, we obtained clinical sample of colon cancer from the TCGA database and cellular senescence-related genes from MSigDB and Genecard datasets. Cellular senescence-related prognostic genes were identified by WGCNA, COX, and lasso regression analysis, and a cellular senescence-related risk score (CSRS) was calculated. We constructed a prognostic model based on CSRS. Validation was performed with an independent cohort that GSE53625. Three scoring systems for immuno-infiltration analysis were performed, namely ssGSEA analysis, ESTIMATE scores and TIDE scores.ResultFive cellular senescence-related genes, including H3C1, IGFBP1, MT1E, SOX5 and CDHR4 and used to calculate risk score. Multivariate regression analysis using cox regression model showed that cellular senescence-related risk scores (HR=2.440, 95% CI=1.154-5.159, p=0.019) and pathological stage (HR=2.423, 95% CI=1.119-5.249, p=0.025) were associated with overall survival (OS). The nomogram model predicts better clinical benefit than the American Joint Committee on Cancer (AJCC) staging for prognosis of patients with esophageal cancer with a five-year AUC of 0.946. Patients with high CSRS had a poor prognosis (HR=2.93, 95%CI=1.74-4.94, p<0.001). We observed differences in the distribution of CSRS in different pathological staging and therefore performed a subgroup survival analysis finding that assessment of prognosis by CSRS independent of pathological staging. Comprehensive immune infiltration analysis and functional enrichment analysis suggested that patients with high CSRS may develop immunotherapy resistance through mechanisms of deacetylation and methylation.DiscussionIn summary, our study suggested that CSRS is a prognostic risk factor for esophageal cancer. Patients with high CSRS may have worse immunotherapy outcomes.

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BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Cited by 17 publications

References 84 publications

BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma

BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma

RNA Polymerase II, the BAF remodeler and transcription factors synergize to evict nucleosomes

Prognostic model construction and validation of esophageal cancer cellular senescence-related genes and correlation with immune infiltration

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