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

Parisian, Alison; Koga, Tomoyuki; Miki, Soichiro; Johann, Pascal; Kool, Marcel; Crawford, John R.; Furnari, Frank B.

doi:10.1101/2020.05.04.074443

Cited by 4 publications

(6 citation statements)

References 41 publications

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“…In fact, data from our group demonstrate that Smarcb1 loss in mice results in severe brain developmental defects when occurring at an early timepoint during embryonic development [76]. In addition, the importance of SMARCB1 for neural development has been shown in human iPSCs [77]. Importantly, Smarcb1 alterations are linked to neurodevelopmental disorders and tumours of the developing brain such as atypical teratoid rhabdoid tumours (AT/RT).…”

Section: Discussionmentioning

confidence: 98%

Smarcb1 Loss Results in a Deregulation of esBAF Binding and Impacts the Expression of Neurodevelopmental Genes

Alfert

Walter

Moreno

et al. 2022

Cells

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The murine esBAF complex plays a major role in the regulation of gene expression during stem cell development and differentiation. As one of its core subunits, Smarcb1 is indispensable for its function and its loss is connected to neurodevelopmental disorders and participates in the carcinogenesis of entities such as rhabdoid tumours. We explored how Smarcb1 regulates gene programs in murine embryonic stem cells (mESC) and in this way orchestrates differentiation. Our data underline the importance of Smarcb1 expression and function for the development of the nervous system along with basic cellular functions, such as cell adhesion and cell organisation. Using ChIP-seq, we were able to portray the consequences of Smarcb1 knockdown (kd) for the binding of esBAF and PRC2 as well as its influence on histone marks H3K27me3, H3K4me3 and H3K27ac. Their signals are changed in gene and enhancer regions of genes connected to nervous system development and offers a plausible explanation for changes in gene expression. Further, we describe a group of genes that are, despite increased BAF binding, suppressed after Smarcb1 kd by mechanisms independent of PRC2 function.

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Section: Discussionmentioning

confidence: 98%

Smarcb1 Loss Results in a Deregulation of esBAF Binding and Impacts the Expression of Neurodevelopmental Genes

Alfert

Walter

Moreno

et al. 2022

Cells

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“…This is in line with our results showing major reorganizations related at a later stage of neural differentiation. Indeed, multiple NDD cell models have shown that the dysfunction of the chromatin organization leads to changed neuronal maturation (Calzari et al, 2020; Parisian et al, 2020; Su et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis

Mastropasqua

Oksanen

Soldini

et al. 2022

Preprint

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Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs); however, the role of HNRNPU in human neural development and NDDs remains to be studied. Here, we describe the molecular and cellular outcomes of HNRNPU deficiency during in vitro neural differentiation of isogenic and patient-derived neuroepithelial stem cells. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show the effects of the molecular reorganization at the cellular level, where HNRNPU downregulation leads to altered neurogenesis and an increased fraction of neural progenitors marked in the maturing neuronal population. We conclude that HNRNPU deficiency is responsible for the delayed commitment of neural progenitors to neuronal maturation, ultimately leading to altered neurogenesis.

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“…Genetically engineered human induced pluripotent stem cells (iPSC) have proven to be an effective, highly customizable system to model gliomagenesis in a species-specific manner, allowing for longitudinal analysis of human tumor biology from potential cell(s) of origin (Koga et al 2020;Miki et al 2022;Parisian et al 2020). Here, we employ an iPSC-based system to show that TP53 loss-and PDGFRA gain-of-function mutations, respectively, cooperate with heterozygous, chromosomal H3.3K27M to potentiate DMG tumor growth and alter cellular metabolism and intracellular signaling.…”

Section: Introductionmentioning

confidence: 99%

Cooperativity between H3.3K27M and PDGFRA poses multiple therapeutic vulnerabilities in human iPSC-derived diffuse midline glioma avatars

Skinner

Koga

Miki

et al. 2023

Preprint

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Diffuse midline glioma (DMG) is a leading cause of brain tumor death in children. In addition to hallmark H3.3K27M mutations, significant subsets also harbor alterations of other genes, such asTP53andPDGFRA. Despite the prevalence of H3.3K27M, the results of clinical trials in DMG have been mixed, possibly due to the lack of models recapitulating its genetic heterogeneity. To address this gap, we developed human iPSC-derived tumor models harboring TP53R248Qwith or without heterozygous H3.3K27M and/or PDGFRAD842Voverexpression. The combination of H3.3K27M and PDGFRAD842Vresulted in more proliferative tumors when gene-edited neural progenitor (NP) cells were implanted into mouse brains compared to NP with either mutation alone. Transcriptomic comparison of tumors and their NP cells of origin identified conserved JAK/STAT pathway activation across genotypes as characteristic of malignant transformation. Conversely, integrated genome-wide epigenomic and transcriptomic analyses, as well as rational pharmacologic inhibition, revealed targetable vulnerabilities unique to the TP53R248Q; H3.3K27M; PDGFRAD842Vtumors and related to their aggressive growth phenotype. These include AREG-mediated cell cycle control, altered metabolism, and vulnerability to combination ONC201/trametinib treatment. Taken together, these data suggest that cooperation between H3.3K27M and PDGFRA influences tumor biology, underscoring the need for better molecular stratification in DMG clinical trials.

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

Cited by 4 publications

References 41 publications

Smarcb1 Loss Results in a Deregulation of esBAF Binding and Impacts the Expression of Neurodevelopmental Genes

Smarcb1 Loss Results in a Deregulation of esBAF Binding and Impacts the Expression of Neurodevelopmental Genes

Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis

Cooperativity between H3.3K27M and PDGFRA poses multiple therapeutic vulnerabilities in human iPSC-derived diffuse midline glioma avatars

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