scholarly journals EWS–FLI1 modulated alternative splicing of ARID1A reveals novel oncogenic function through the BAF complex

2019 ◽  
Author(s):  
Saravana P Selvanathan ◽  
Garrett T Graham ◽  
Alexander R Grego ◽  
Tabari M Baker ◽  
J Robert Hogg ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Tumor Suppressors ◽  
Drug Targeting ◽  
Mrna Isoforms ◽  
Protein Variant ◽  
Baf Complex ◽  
Oncogenic Driver ◽  
Precise Role ◽  
Oncogenic Function

Abstract Connections between epigenetic reprogramming and transcription or splicing create novel mechanistic networks that can be targeted with tailored therapies. Multiple subunits of the chromatin remodeling BAF complex, including ARID1A, play a role in oncogenesis, either as tumor suppressors or oncogenes. Recent work demonstrated that EWS–FLI1, the oncogenic driver of Ewing sarcoma (ES), plays a role in chromatin regulation through interactions with the BAF complex. However, the specific BAF subunits that interact with EWS–FLI1 and the precise role of the BAF complex in ES oncogenesis remain unknown. In addition to regulating transcription, EWS–FLI1 also alters the splicing of many mRNA isoforms, but the role of splicing modulation in ES oncogenesis is not well understood. We have identified a direct connection between the EWS–FLI1 protein and ARID1A isoform protein variant ARID1A-L. We demonstrate here that ARID1A-L is critical for ES maintenance and supports oncogenic transformation. We further report a novel feed-forward cycle in which EWS–FLI1 leads to preferential splicing of ARID1A-L, promoting ES growth, and ARID1A-L reciprocally promotes EWS–FLI1 protein stability. Dissecting this interaction may lead to improved cancer-specific drug targeting.

scholarly journals Conditional Loss of BAF (mSWI/SNF) Scaffolding Subunits Affects Specification and Proliferation of Oligodendrocyte Precursors in Developing Mouse Forebrain

2021 ◽  
Vol 9 ◽  
Author(s):  
Eman Abbas ◽  
Mohamed A. Hassan ◽  
Godwin Sokpor ◽  
Kamila Kiszka ◽  
Linh Pham ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Neural Development ◽  
Conditional Knockout ◽  
Baf Complex ◽  
Ventral Telencephalon ◽  
Mouse Mutants ◽  
Oligodendrocyte Precursor ◽  
Brain And Spinal Cord ◽  
The Brain

Oligodendrocytes are responsible for axon myelination in the brain and spinal cord. Generation of oligodendrocytes entails highly regulated multistage neurodevelopmental events, including proliferation, differentiation and maturation. The chromatin remodeling BAF (mSWI/SNF) complex is a notable regulator of neural development. In our previous studies, we determined the indispensability of the BAF complex scaffolding subunits BAF155 and BAF170 for neurogenesis, whereas their role in gliogenesis is unknown. Here, we show that the expression of BAF155 and BAF170 is essential for the genesis of oligodendrocytes during brain development. We report that the ablation of BAF155 and BAF170 in the dorsal telencephalic (dTel) neural progenitors or in oligodendrocyte-producing progenitors in the ventral telencephalon (vTel) in double-conditional knockout (dcKO) mouse mutants, perturbed the process of oligodendrogenesis. Molecular marker and cell cycle analyses revealed impairment of oligodendrocyte precursor specification and proliferation, as well as overt depletion of oligodendrocytes pool in dcKO mutants. Our findings unveil a central role of BAF155 and BAF170 in oligodendrogenesis, and thus substantiate the involvement of the BAF complex in the production of oligodendrocytes in the forebrain.

scholarly journals Intrinsic Disorder of the BAF Complex: Roles in Chromatin Remodeling and Disease Development

2019 ◽  
Vol 20 (21) ◽  
pp. 5260 ◽  
Author(s):  
El Hadidy ◽  
Uversky
Keyword(s):  
Chromatin Remodeling ◽  
Regulation Of Gene Expression ◽  
Intrinsic Disorder ◽  
Literature Mining ◽  
Baf Complex ◽  
Chromatin Remodeling Complex ◽  
Significant Barrier ◽  
Polymorphic Structure ◽  
Chromatin Reorganization

The two-meter-long DNA is compressed into chromatin in the nucleus of every cell, which serves as a significant barrier to transcription. Therefore, for processes such as replication and transcription to occur, the highly compacted chromatin must be relaxed, and the processes required for chromatin reorganization for the aim of replication or transcription are controlled by ATP-dependent nucleosome remodelers. One of the most highly studied remodelers of this kind is the BRG1- or BRM-associated factor complex (BAF complex, also known as SWItch/sucrose non-fermentable (SWI/SNF) complex), which is crucial for the regulation of gene expression and differentiation in eukaryotes. Chromatin remodeling complex BAF is characterized by a highly polymorphic structure, containing from four to 17 subunits encoded by 29 genes. The aim of this paper is to provide an overview of the role of BAF complex in chromatin remodeling and also to use literature mining and a set of computational and bioinformatics tools to analyze structural properties, intrinsic disorder predisposition, and functionalities of its subunits, along with the description of the relations of different BAF complex subunits to the pathogenesis of various human diseases.

scholarly journals Microtubular and Nuclear Functions of γ-Tubulin: Are They LINCed?

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 259 ◽  
Author(s):  
Jana Chumová ◽  
Hana Kourová ◽  
Lucie Trögelová ◽  
Petr Halada ◽  
Pavla Binarová
Keyword(s):  
Chromatin Remodeling ◽  
Dna Damage Response ◽  
Tumor Suppressors ◽  
Molecular Mechanisms ◽  
Nuclear Organization ◽  
Linc Complex ◽  
Cellular Functions ◽  
Microtubule Nucleation ◽  
Damage Response

γ-Tubulin is a conserved member of the tubulin superfamily with a function in microtubule nucleation. Proteins of γ-tubulin complexes serve as nucleation templates as well as a majority of other proteins contributing to centrosomal and non-centrosomal nucleation, conserved across eukaryotes. There is a growing amount of evidence of γ-tubulin functions besides microtubule nucleation in transcription, DNA damage response, chromatin remodeling, and on its interactions with tumor suppressors. However, the molecular mechanisms are not well understood. Furthermore, interactions with lamin and SUN proteins of the LINC complex suggest the role of γ-tubulin in the coupling of nuclear organization with cytoskeletons. γ-Tubulin that belongs to the clade of eukaryotic tubulins shows characteristics of both prokaryotic and eukaryotic tubulins. Both human and plant γ-tubulins preserve the ability of prokaryotic tubulins to assemble filaments and higher-order fibrillar networks. γ-Tubulin filaments, with bundling and aggregating capacity, are suggested to perform complex scaffolding and sequestration functions. In this review, we discuss a plethora of γ-tubulin molecular interactions and cellular functions, as well as recent advances in understanding the molecular mechanisms behind them.

Tumor suppressor role of chromatin-remodeling factor ARID1A

2013 ◽  
Vol 35 (3) ◽  
pp. 255-261 ◽  
Author(s):  
Xiao-Qiang GUO ◽  
Qiao-Xia ZHANG ◽  
Wei-Ren HUANG ◽  
Xiang-Lin DUAN ◽  
Zhi-Ming CAI
Keyword(s):  
Tumor Suppressor ◽  
Chromatin Remodeling

scholarly journals The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaoping Xu ◽  
Kai Ni ◽  
Yafeng He ◽  
Jianke Ren ◽  
Chongkui Sun ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Critical Role ◽  
Genomic Stability ◽  
Dna Degradation ◽  
Replication Forks ◽  
Filament Formation ◽  
Epigenetic Regulator ◽  
Centromeric Instability ◽  
Stalled Replication Forks

AbstractThe Immunodeficiency Centromeric Instability Facial Anomalies (ICF) 4 syndrome is caused by mutations in LSH/HELLS, a chromatin remodeler promoting incorporation of histone variant macroH2A. Here, we demonstrate that LSH depletion results in degradation of nascent DNA at stalled replication forks and the generation of genomic instability. The protection of stalled forks is mediated by macroH2A, whose knockdown mimics LSH depletion and whose overexpression rescues nascent DNA degradation. LSH or macroH2A deficiency leads to an impairment of RAD51 loading, a factor that prevents MRE11 and EXO1 mediated nascent DNA degradation. The defect in RAD51 loading is linked to a disbalance of BRCA1 and 53BP1 accumulation at stalled forks. This is associated with perturbed histone modifications, including abnormal H4K20 methylation that is critical for BRCA1 enrichment and 53BP1 exclusion. Altogether, our results illuminate the mechanism underlying a human syndrome and reveal a critical role of LSH mediated chromatin remodeling in genomic stability.

scholarly journals Cholinergic Signaling, Neural Excitability, and Epilepsy

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2258
Author(s):  
Yu Wang ◽  
Bei Tan ◽  
Yi Wang ◽  
Zhong Chen
Keyword(s):  
Cholinergic Neurons ◽  
Epileptic Seizures ◽  
Brain Disorder ◽  
Neural Excitability ◽  
Cholinergic Signaling ◽  
The Central Nervous System ◽  
Muscarinic And Nicotinic Receptors ◽  
Cumulative Evidence ◽  
Precise Role

Epilepsy is a common brain disorder characterized by recurrent epileptic seizures with neuronal hyperexcitability. Apart from the classical imbalance between excitatory glutamatergic transmission and inhibitory γ-aminobutyric acidergic transmission, cumulative evidence suggest that cholinergic signaling is crucially involved in the modulation of neural excitability and epilepsy. In this review, we briefly describe the distribution of cholinergic neurons, muscarinic, and nicotinic receptors in the central nervous system and their relationship with neural excitability. Then, we summarize the findings from experimental and clinical research on the role of cholinergic signaling in epilepsy. Furthermore, we provide some perspectives on future investigation to reveal the precise role of the cholinergic system in epilepsy.

scholarly journals FOXO1 mitigates the SMAD3/FOXL2C134W transcriptomic effect in a model of human adult granulosa cell tumor

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Christian Secchi ◽  
Paola Benaglio ◽  
Francesca Mulas ◽  
Martina Belli ◽  
Dwayne Stupack ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Chromatin Remodeling ◽  
Granulosa Cell Tumor ◽  
Cell Tumor ◽  
Rna Seq ◽  
Pathogenic Role ◽  
Rare Type ◽  
Cellular Models ◽  
Genome Wide

Abstract Background Adult granulosa cell tumor (aGCT) is a rare type of stromal cell malignant cancer of the ovary characterized by elevated estrogen levels. aGCTs ubiquitously harbor a somatic mutation in FOXL2 gene, Cys134Trp (c.402C < G); however, the general molecular effect of this mutation and its putative pathogenic role in aGCT tumorigenesis is not completely understood. We previously studied the role of FOXL2C134W, its partner SMAD3 and its antagonist FOXO1 in cellular models of aGCT. Methods In this work, seeking more comprehensive profiling of FOXL2C134W transcriptomic effects, we performed an RNA-seq analysis comparing the effect of FOXL2WT/SMAD3 and FOXL2C134W/SMAD3 overexpression in an established human GC line (HGrC1), which is not luteinized, and bears normal alleles of FOXL2. Results Our data shows that FOXL2C134W/SMAD3 overexpression alters the expression of 717 genes. These genes include known and novel FOXL2 targets (TGFB2, SMARCA4, HSPG2, MKI67, NFKBIA) and are enriched for neoplastic pathways (Proteoglycans in Cancer, Chromatin remodeling, Apoptosis, Tissue Morphogenesis, Tyrosine Kinase Receptors). We additionally expressed the FOXL2 antagonistic Forkhead protein, FOXO1. Surprisingly, overexpression of FOXO1 mitigated 40% of the altered genome-wide effects specifically related to FOXL2C134W, suggesting it can be a new target for aGCT treatment. Conclusions Our transcriptomic data provide novel insights into potential genes (FOXO1 regulated) that could be used as biomarkers of efficacy in aGCT patients.

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