Loss of BAF (mSWI/SNF) complexes causes global transcriptional and chromatin state changes in forebrain development
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE73855 | GEO | 2015/10/09
SECONDARY ACCESSION(S): PRJNA298228
REPOSITORIES: GEO
Similar Datasets
Project description:We have analyzed changes in gene expression, histone 3 lysine 4 dimethyl (H3K4me2) and histone 3 lysine 37 trimethyl (H3K27me3) levels in the embryonic cortex at E17.5 resulting from conditional deletion of BAF complex - i.e., double knockout of BAF155 and BAF170, in late cortical progenitors utilizing Cre expression under human GFAP (hGFAP) promoter (dcKO_hGFAP-Cre). Moreover, we also analyzed gene expression in WT E17.5 cortex treated with vehicle and Wnt inhibitor together with that of in dcKO_hGFAP-Cre cortex treated with Wnt inhibitor. Gene expression studies were conducted by RNA-Seq and histone marks were analyzed by ChIP-Seq.
2018-04-22 | GSE106711 | GEO
Project description:The persistence of a pool of latently HIV-1-infected cells despite combination anti-retroviral therapy treatment is the major roadblock for a cure. The BAF (mammalian SWI/SNF) chromatin remodeling complex is involved in establishing and maintaining viral latency, making it an attractive drug target for HIV-1 latency reversal. Here we report a high-throughput screen for inhibitors of BAF-mediated transcription in cells and the subsequent identification of a 12-membered macrolactam. This compound binds ARID1A-specific BAF complexes, prevents nucleosomal positioning, and relieves transcriptional repression of HIV-1. Through this mechanism, these compounds are able to reverse HIV-1 latency in an in vitro T cell line, an ex vivo primary cell model of HIV-1 latency, and in patient CD4+ T cells without toxicity or T cell activation. These macrolactams represent a class of latency reversal agents with unique mechanism of action, and can be combined with other latency reversal agents to improve reservoir targeting.
| S-EPMC6404985 | biostudies-literature
Project description:The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development.
| S-EPMC4889280 | biostudies-literature
Project description:Recent exon sequencing studies of human tumors have revealed that subunits of mSWI/SNF or BAF complexes are mutated in more than 20% of human malignancies, yet the mechanisms involved in tumor suppression is unclear. BAF chromatin remodeling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure and the placement of Polycomb (PcG) across the genome. Several proteins dedicated to this large multi-subunit complex, including SMARCA4 (BRG1) and BAF250A (ARID1A), are mutated at frequencies similar to that of many recognized tumor suppressors. In particular, the core ATPase BRG1 is mutated in 5-10% of childhood medulloblastoma (MB) and greater than 15% of Burkitt's Lymphoma (BL). Here we find a novel function of BAF complexes in decatenating newly replicated sister chromatids, which is necessary for proper chromosome segregation during mitosis. We find that deletion of Brg1, as well as the expression of Brg1 point mutants identified in human tumors leads to anaphase bridge formation (sister chromatids linked by catenated strands of DNA), and a G2/M phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes directly interact with endogenous TopoIIα through BAF250a and are required for TopoIIα binding to about 12,000 sites over the genome. Our results indicate that TopoIIα’s chromatin binding is dependent on the ATPase activity of Brg1, which is compromised in oncogenic Brg1 mutants. These studies indicate that the ability of TopoIIα to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of BAF subunits as tumor suppressors. Examination of sites of TopoIIa activity in WT and Brg1-/- ES cells as defined by TopoIIa-DNA covalent adducts formed in the presence of etoposide
2013-03-30 | E-GEOD-45625 | biostudies-arrayexpress
Project description:Neurogenesis is a key developmental event through which neurons are generated from neural stem/progenitor cells. Chromatin remodeling BAF (mSWI/SNF) complexes have been reported to play essential roles in the neurogenesis of the central nervous system. However, whether BAF complexes are required for neuron generation in the olfactory system is unknown. Here, we identified onscBAF and ornBAF complexes, which are specifically present in olfactory neural stem cells (oNSCs) and olfactory receptor neurons (ORNs), respectively. We demonstrated that BAF155 subunit is highly expressed in both oNSCs and ORNs, whereas high expression of BAF170 subunit is observed only in ORNs. We report that conditional deletion of BAF155, a core subunit in both onscBAF and ornBAF complexes, causes impaired proliferation of oNSCs as well as defective maturation and axonogenesis of ORNs in the developing olfactory epithelium (OE), while the high expression of BAF170 is important for maturation of ORNs. Interestingly, in the absence of BAF complexes in BAF155/BAF170 double-conditional knockout mice (dcKO), OE is not specified. Mechanistically, BAF complex is required for normal activation of Pax6-dependent transcriptional activity in stem cells/progenitors of the OE. Our findings unveil a novel mechanism mediated by the mSWI/SNF complex in OE neurogenesis and development.
| S-EPMC5017785 | biostudies-literature
Project description:Chromatin remodeling molecules of the BAF complex, Brg1 and Baf155, as well as other chromatin remodeling modeling molecules have been described to enhance Oct4, Sox2, Klf4 and c-Myc mediated reprogramming of mouse somatic cells into induced pluripotent stem cells (iPSCs). Brg1 maintains pluripotency of mouse embryonic stem cells (mESCs) by modulating the expression of pluripotency genes including Oct4 in synergism with LIF/STAT signaling. Interestingly, unlike mESCs, BAF complex in human embryonic stem cells (hESCs) is composed of both BAF155 and BAF170, where BAF170 plays a role in maintaining hESCs pluripotency. In this study, we describe that BRG1 and BAF155 enhance reprogramming of adult human fibroblasts. Overexpression of BAF155 does not affect pluripotency of hiPSCs as tested by global gene expression profiling as well as in vivo and in vitro assays. Additionally, these findings show that BRG1 and BAF155 expression can enhance reprogramming even in the absence of LIF/STAT signaling.
2018-11-29 | GSE75568 | GEO
Project description:Recent exon sequencing studies have revealed that over 20% of human tumors have mutations in subunits of mSWI/SNF (BAF) complexes. To investigate the underlying mechanism, we studied human synovial sarcoma (SS), in which transformation results from the translocation of exactly 78 amino acids of SSX to the SS18 subunit of BAF complexes. We demonstrate that the SS18-SSX fusion protein competes for assembly with wild-type SS18, forming an altered complex lacking the tumor suppressor BAF47 (hSNF5). The altered complex binds the Sox2 locus and reverses polycomb-mediated repression, resulting in Sox2 activation. Sox2 is uniformly expressed in SS tumors and is essential for proliferation. Increasing the concentration of wild-type SS18 leads to reassembly of wild-type complexes retargeted away from the Sox2 locus, polycomb-mediated repression of Sox2, and cessation of proliferation. This mechanism of transformation depends on only two amino acids of SSX, providing a potential foundation for therapeutic intervention.
| S-EPMC3655887 | biostudies-literature
Project description: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.
| S-EPMC8320002 | biostudies-literature
Project description:The Brg/Brahma-associated factor (BAF, mSWI/SNF) chromatin remodeling complex is of importance in development and has been linked to prostate oncogenesis. The oncogenic MUC1-C protein promotes lineage plasticity in the progression of neuroendocrine prostate cancer (NEPC), however, there is no known association between MUC1-C and BAF. We report here that MUC1-C binds directly to the E2F1 transcription factor and that the MUC1-C→E2F1 pathway induces expression of embryonic stem cell-specific BAF (esBAF) components BRG1, ARID1A, BAF60a, BAF155, and BAF170 in castrate-resistant prostate cancer (CRPC) and NEPC cells. In concert with this previously unrecognized pathway, MUC1 was associated with increased expression of E2F1 and esBAF components in NEPC tumors as compared with CRPC, supporting involvement of MUC1-C in activating the E2F1→esBAF pathway with progression to NEPC. MUC1-C formed a nuclear complex with BAF and activated cancer stem cell (CSC) gene signatures and the core pluripotency factor gene network. The MUC1-C→E2F1→BAF pathway was necessary for induction of both the NOTCH1 effector of CSC function and the NANOG pluripotency factor, and collectively, this network drove CSC self-renewal. These findings indicate that MUC1-C promotes NEPC progression by integrating activation of E2F1 and esBAF with induction of NOTCH1, NANOG, and stemness. SIGNIFICANCE: These findings show that MUC1-C, which promotes prostate cancer progression, activates a novel pathway that drives the BAF remodeling complex, induces NOTCH1 and NANOG, and promotes self-renewal of prostate cancer stem cells.
| S-EPMC8026569 | biostudies-literature
Project description:Recent exon sequencing studies of human tumors have revealed that subunits of mSWI/SNF or BAF complexes are mutated in more than 20% of human malignancies, yet the mechanisms involved in tumor suppression is unclear. BAF chromatin remodeling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure and the placement of Polycomb (PcG) across the genome. Several proteins dedicated to this large multi-subunit complex, including SMARCA4 (BRG1) and BAF250A (ARID1A), are mutated at frequencies similar to that of many recognized tumor suppressors. In particular, the core ATPase BRG1 is mutated in 5-10% of childhood medulloblastoma (MB) and greater than 15% of Burkitt's Lymphoma (BL). Here we find a novel function of BAF complexes in decatenating newly replicated sister chromatids, which is necessary for proper chromosome segregation during mitosis. We find that deletion of Brg1, as well as the expression of Brg1 point mutants identified in human tumors leads to anaphase bridge formation (sister chromatids linked by catenated strands of DNA), and a G2/M phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes directly interact with endogenous TopoIIα through BAF250a and are required for TopoIIα binding to about 12,000 sites over the genome. Our results indicate that TopoIIα’s chromatin binding is dependent on the ATPase activity of Brg1, which is compromised in oncogenic Brg1 mutants. These studies indicate that the ability of TopoIIα to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of BAF subunits as tumor suppressors.
2013-03-30 | GSE45625 | GEO