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SMARCB1 loss interacts with neuronal differentiation state to block maturation in an organoid model

ABSTRACT: SMARCB1 loss interacts with neuronal differentiation state to block maturation in an organoid model

PROVIDER: PRJNA661565 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12594375.fastq.gz	Fastqsanger.gz
	SRR12594376.fastq.gz	Fastqsanger.gz
	SRR12594377.fastq.gz	Fastqsanger.gz
	SRR12594378.fastq.gz	Fastqsanger.gz
	SRR12594379.fastq.gz	Fastqsanger.gz

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SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability

Project description:SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability

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SMARCB1 loss interacts with neuronal differentiation state to block maturation in an organoid model

Project description:We conducted 10X single-cell RNA sequencing of control organoids and organoids differentiated with SMARCB1 knockdown from Day 0 of protocol

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SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability

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SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability.

Project description:Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SMARCB1 loss and the process of neural development, we introduced an inducible SMARCB1 loss-of-function system into human induced pluripotent stem cells (iPSCs) that were subjected to either directed neuronal differentiation or differentiation into cerebral organoids. Using this system, we identified substantial differences in the downstream effects of SMARCB1 loss depending on differentiation state and identified an interaction between SMARCB1 loss and neural differentiation pressure that causes a resistance to terminal differentiation and a defect in maintenance of a normal cell state. Our results provide insight into how SMARCB1 loss might interact with neural development in the process of ATRT tumorigenesis.

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Transcriptional response to Smarcb1 re-expression in murine derived Smarcb1 deficient p53 null tumors

Project description:SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice. Profiling Smarcb1 dependent gene expression we find genes which are dependent on Smarcb1 expression to be enriched for ECM and cell adhesion functions. We identify Igfbp7, which is related to the insulin-like growth factor binding proteins family, as a downstream target of Smarcb1 transcriptional activity, and show that re-introduction of Igfbp7 alone can hinder tumor development. Two cancer cell lines, 167 and 365, derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice were re-infected with a retro-viral vector for Smarcb1 re-expression or an empty retro-viral vector as control. Total-RNA was collected 3 days post infection so as to enrich for direct targets of Smarcb1 transcriptionaly regulated genes

2013-12-31 | E-GEOD-46017 | biostudies-arrayexpress

Gene expression analysis of human haploid cells (HAP1) depleted of SMARCB1 and SMARCA4

Project description:The aim of this study is to analyze the change in genome wide expression levels in HAP1 cells upon loss of SMARCB1, SMARCA4 or both these genes together. The SMARCB1 and SMARCA4 genes were the hits from a genome wide screen involving genetrap mutagenesis to find new players that are involved in sensitivity to Doxorubicin (Dox). It was found that loss of SMARCB1 and SMARCA4 genes impart resistance in HAP1 cells to Dox. To validate this, the genes were knocked out in HAP1 cells with CRISPR-Cas9 technology. Gene expression levels in SMARCB1 null, SMARCA4 null and SMARCB1-SMARCA4 double null cells were compared to wildtype HAP1 cells using RNAseq. From these experiments it was found that SMARCB1 loss caused several fold increase in ABCB1 gene levels. ABCB1 is an efflux pump in cells responsible for flushing out many small-molecule drugs. Further analysis of this gene confirmed that ABCB1 was the main factor responsible for Dox resistance upon SMARCB1 loss. In total there are four different cell types with two replicates for each cell type. Therefore, 8 samples in total.

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Volumetric compression by heterogeneous scaffold embedding promotes cerebral organoid growth and maturation

Project description:While biochemical regulation has been extensively studied in cerebral organoid modeling protocols, the role of mechano-regulation in directing stem cell fate and organoid development has been relatively unexplored. Volumetric compression, a key aspect of natural brain development, is known to influence neuronal differentiation. However, stiff interpenetrating network compression fails to accurately replicate the dynamic organoid development observed in nature. In this study, we present a novel method of heterogeneous embedding using an alginate-shell-Matrigel-core system. This approach allows for cell-Matrigel remodeling by the inner layer and provides moderate normal compression through the soft alginate outer layer. Our results show significant improvements in cell proliferation and maturation of cerebral organoids, as evidenced by increased expression of neuronal markers such as neurofilament (NF) and microtubule-associated protein 2 (MAP2). Compared to non-alginate embedding and alginate compression groups, volume growth remains unimpeded. Our findings demonstrate the successful mechanical regulation of cerebral organoids, which not only mimics the mechanical environment of brain development but also exhibits a regular growth profile with enhanced maturation. These results highlight the importance and potential practical applications of mechano-regulation in the establishment of brain organoids.

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Transcriptional response to Smarcb1 re-expression in murine derived Smarcb1 deficient p53 null tumors

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mSWI/SNF functional genomic characterization of SMARCB1 mutants in SMARCB1-null and heterozygous settings

Project description:Chromatin remodeling complexes regulate gene expression by shifting, evicting, and exchanging nucleosomes along the chromosomes of eukaryotic organisms. The mammalian SWI/SNF chromatin remodeling complex (mSWI/SNF or BAF) is mutated in over 20% of human cancers and loss of the SMARCB1 gene, encoding the BAF47 protein subunit, results in one of the most aggressive and lethal pediatric cancers. An accumulation of point mutations occurs at the C-terminal end of the protein, for which the functional ramifications are unknown. We previously demonstrated that reintroduction of SMARCB1 in SMARCB1-null malignant rhabdoid tumor cells results in a genome-wide increase of mSWI/SNF complex occupancy coupled with activation of PRC2-repressed genes. Here, we study the functional consequences that these point mutations exert on mSWI/SNF complex activity in SMARCB1-deficient tumor cells and extend this investigation to a CRISPR/Cas9-mediated SMARCB1-heterozygous mutant induced pluripotent stem cell. Intriguingly, we observe that the mutant complexes bind similarly to wild-type SMARCB1 complexes at enhancers throughout the genome but often fail to transcriptionally activate nearby genes in a cis-regulatory manner.

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Single-cell analysis of human iPSC-derived multi-lineage mini-cardiac organoid reveals molecular pathways to promote cardiomyocyte maturation and heart repair

Project description:Human induced pluripotent stem cell (hiPSC)-derived cardiovascular cells are promising cell source for cell therapy to repair the heart. Cardiac microtissue consisted of cardiomyocytes and fibroblast cells exhibited much better physiological functions. How different cardiovascular cell types interact and evolve in 3D microenvironment is unknown. In this study, we performed single-cell transcriptome profiling of hiPSC-derived mini-cardiac organoid consisted of cardiomyocytes, endothelial cells and smooth muscle cells. Our analysis showed that cardiac fibroblasts emerged spontaneously in 3D microenvironment which in turn facilitated the maturation of cardiomyocytes. HiPSC-derived cardiomyocytes, endothelial cells and smooth muscle cells assembled into mini-cardiac organoid in collagen-matrigel after 2 weeks. Single-cell study uncovered significant cell fate shift and improvement in cardiomyocyte maturation status upon-multilineage co-culture. Ligand-receptor analysis identified DLK1-Notch signaling to be one of the most upregulated pathways in the fibroblast population. Modulate the activity of DLK1-Notch signaling affected the assembly of the mini-cardiac organoid and the expression of immune regulatory genes. Interestingly, transplantation of trilineage mini-cardiac organoid into a rat model of myocardial infarction leads to significant improvement of cardiac function. Collectively, our single-cell analysis of mini-cardiac organoid provided rich information about cell fate dynamics and multilineage cross-talks occurred in the 3D microenvironment, which bring new insight on the molecular mechanism that promotes cardiomyocyte maturation and heart repair.

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