Brg1

Chromatin-remodeling protein BRG1/SMARCA4 is pivotal for establishing oligodendrocyte (OL) lineage identity. However, its functions for oligodendrocyte-precursor cell (OPC) differentiation within the postnatal brain and during remyelination remain elusive. Here, we demonstrate that Brg1 loss profoundly impairs OPC differentiation in the brain with a comparatively lesser effect in the spinal cord. Moreover, BRG1 is critical for OPC remyelination after injury. Integrative transcriptomic/genomic profiling reveals that BRG1 exhibits a dual role by promoting OPC differentiation networks while repressing OL-inhibitory cues and proneuronal programs...

Endometrial somatically derived yolk sac tumors are characterized by yolk sac morphology with AFP, SALL-4, and/or Glypican-3 immunoexpression. Yolk sac marker expression, however, is not limited to tumors with overt yolk sac histology. Three hundred consecutive endometrial malignancies were assessed for immunomarkers of yolk sac differentiation. Of these, 9% expressed ≥1 yolk sac marker, including 29% of high-grade tumors. Only 3 (1%) met morphologic criteria for yolk sac differentiation; these were originally diagnosed as serous, high-grade NOS, and dedifferentiated carcinoma...

The clinicopathological spectrum of undifferentiated round cell sarcomas of bone and soft tissues is expanding after the 5th edition of the WHO classification. A 23-year-old male patient presented with a lump in his left thigh of 3 months' duration. Radiological examination revealed a well-defined, solid-cystic lobulated, soft tissue lesion in the proximal medial region of his left thigh, measuring 7.7 cm in the largest dimension. The referring diagnosis was an epithelioid sarcoma. Histopathological review of the tumor sections revealed a cellular tumor composed of malignant epithelioid to focally "rhabdoid-like" cells in a variable hyalinized and myxoid stroma with geographic areas of necrosis...

AIMS: Hepatocellular carcinoma (HCC) is a lead cause of cancer-related deaths. In the present study we investigated the role of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in HCC the pathogenesis focusing on identifying novel transcription targets. METHODS AND MATERIALS: Hepatocellular carcinogenesis was modeled in mice by diethylnitrosamine (DEN). Cellular transcriptome was evaluated by RNA-seq. RESULTS: Hepatocellular carcinoma was appreciably retarded in BRG1 knockout mice compared to wild type littermates...

AIMS: To investigate the key factors influencing glioma progression and the emergence of treatment resistance by examining the intrinsic connection between mutations in DNA damage and repair-related genes and the development of chemoresistance in gliomas. METHODS: We conducted a comprehensive analysis of deep-targeted gene sequencing data from 228 glioma samples. This involved identifying differentially mutated genes across various glioma grades, assessing their functions, and employing I-TASSER for homology modeling...

RNA transcribed from enhancers, i.e., eRNA, has been suggested to directly activate transcription by recruiting transcription factors and co-activators. Although there have been specific examples of eRNA functioning in this way, it is not clear how general this may be. We find that the AT-hook of SWI/SNF preferentially binds RNA and, as part of the esBAF complex, associates with eRNA transcribed from intronic and intergenic regions. Our data suggest that SWI/SNF is globally recruited in cis by eRNA to cell-type-specific enhancers, representative of two distinct stages that mimic early mammalian development, and not at enhancers that are shared between the two stages...

INTRODUCTION: The multi-subunit SWI/SNF chromatin remodeling complex is a key epigenetic regulator for many cellular processes, and several subunits are found to be mutated in human cancers. The inactivating mutations of SMARCA4, the ATPase subunit of the complex, result in cellular dependency on the paralog SMARCA2 for survival. This observed synthetic lethal relationship posits targeting SMARCA2 in SMARCA4-deficient settings as an attractive therapeutic target in oncology. AREAS COVERED: This review covers patent literature disclosed during the 2019-30 June 2023 period which claim ATPase inhibitors and PROTAC degraders that bind to the ATPase domain of SMARCA2 and/or SMARCA4...

BACKGROUND: SMARCA4 is a component of chromatin remodeling of SWItch/sucrose-nonfermenting (SWI/SNF) complexes and plays an essential role in oncogenesis. SMARCA4-deficient malignancies arising from the gastrointestinal tract are rare and have a poor prognosis. There is no standard treatment for advanced and undifferentiated SMARCA4-deficient duodenal malignancies. Programmed death 1 (PD-1) antibodies, known as immune checkpoint inhibitor antibodies, potentially play a role in treating gastrointestinal tract malignancies...

Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including the motor neuron disease, amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TDP-43G348C , FUSR521G or SOD1G93A ...

BACKGROUND: Dilated cardiomyopathy (DCM) and coronary heart disease (CHD) stand as two of the foremost causes of mortality. However, the comprehensive comprehension of the regulatory mechanisms governing DCM and CHD remains limited, particularly from the vantage point of single-cell transcriptional analysis. METHOD: We used the GSE121893 dataset from the GEO database, analyzing single-cell expressions with tools like DropletUtils, Seurat, and Monocle. We also utilized the GSVA package for comparing gene roles in DCM and CHD, Finally, we conducted qRT-PCR and Western blot analyses to measure the expression levels of SMARCA4, Col1A1, Col3A1 and α-SMA, and the role of SMARCA4 on fibroblasts were explored by EdU and Transwell assay...

In the course of our investigations of antifungal natural products, the structure-activity relationship and antifungal activities of oleanolic acid-type saponins (1-28) from Pulsatilla chinensis against human and plant pathogenic fungi were elucidated. The analysis of structure-activity relationship of oleanolic acid-type saponins showed that the free carboxyl at C-28 was essential for their antifungal activities; the free hydroxyl group at the C-23 site of oleanolic acid-type saponins played a crucial role in their antifungal activities; the oligosaccharide chain at C-3 oleanolic acid-type saponins showed significant effects on antifungal efficacy and a disaccharide or trisaccharide moiety at position C-3 displayed optimal antifungal activity...

AIMS: Diabetic nephropathy (DN) is one of the most common complications of diabetes and represents a prototypical form of chronic kidney disease (CKD). Extensive interstitial fibrosis is a key pathological feature of DN. During DN-associated renal fibrosis, resident fibroblasts trans-differentiate into myofibroblasts to remodel the extracellular matrix, the underlying epigenetic mechanism of which is not entirely clear. METHODS: Diabetic nephropathy was induced C57B6/j mice by a single injection with streptozotocin (STZ)...

The process of induced pluripotent stem cells (iPSCs) reprogramming involves several crucial events, including the mesenchymal-epithelial transition (MET), activation of pluripotent genes, metabolic reprogramming, and epigenetic rewiring. Although these events intricately interact and influence each other, the specific element that regulates the reprogramming network remains unclear. Dux, a factor known to promote totipotency during the transition from embryonic stem cells (ESC) to 2C-like ESC (2CLC), has not been extensively studied in the context of iPSC reprogramming...

Molecularly defined neoplasms are increasingly recognized, given the broader application and performance of molecular studies. These studies allow us to better characterize these neoplasms and learn about their pathogenesis. In the thorax, molecularly defined neoplasms include tumors such as NUT carcinoma, SMARCA4-deficient undifferentiated tumor (DUT), primary pulmonary myxoid sarcoma with EWSR1::CREB1 fusion, hyalinizing clear cell carcinoma, and SMARCB1-deficient neoplasms. Overall, these tumors are rare but are now more often recognized given more widely available immunostains such as NUT (NUT carcinoma), BRG1 (SMARCA4-DUT), and INI-1 (SMARCB1-deficient neoplasm)...

SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are a newly described entity and are typically seen in the thoracic cavity. However, these tumors have been described in other body sites, including the esophagus. These tumors are rare, aggressive neoplasms, characterized by the loss of protein product of SMARCA4 (Brahma-related gene-1) and the preservation of INI1 (SMARCB1) expression. Here, we present two tumors of SMARCA4-UT of the esophagus with its microscopic appearance and immunohistochemical profile...

BACKGROUND: SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a class of high-grade malignant tumors that has only been described in recent years, with an undifferentiated or rhabdoid morphology and genetic deletion of SMARCA4 ( BRG1 ), a subunit of the BRG1 -associated factors (BAFs) chromatin remodeling complex. It is a rare tumor type that occurs in young to middle-aged men and usually presents as a compressive thoracic mass with rapid progression and poor prognosis. However, much remains unknown about the clinical and imaging manifestations of the disease...

Mutations in the SWI/SNF chromatin remodeling complex occur in ~20% of cancers. In rhabdoid tumors defined by loss of the SWI/SNF subunit SMARCB1 , dysregulation of enhancer-mediated gene expression is pivotal in driving oncogenesis. Enhancer dysregulation in this setting is tied to retention of the SWI/SNF ATPase BRG1-which becomes essential in the absence of SMARCB1 -but precisely how BRG1 contributes to this process remains unknown. To characterize how BRG1 participates in chromatin remodeling and gene expression in SMARCB1 -deficient cells, we performed a genome-wide characterization of the impact of BRG1 depletion in multiple rhabdoid tumor cell lines...

Candida albicans is a prominent fungal pathogen that can infect the bloodstream and deep tissues. One key pathogenicity trait is the ability to transition between yeast and hyphal growth. Hyphae are critical for the formation of biofilms, which in turn enable device-associated infection. Among signals that drive hypha formation is the presence of hemin, an oxidized Fe(III)-containing heme derivative found in blood. In this study we asked four questions. First, how uniform is the filamentation response to hemin among C...

The Polybromo, BRG1-associated factors (PBAF) chromatin remodeling complex subunit Polybromo-1 (PBRM1) contains six bromodomains that recognize and bind acetylated lysine residues on histone tails and other nuclear proteins. PBRM1 bromodomains thus provide a link between epigenetic post-translational modifications and PBAF modulation of chromatin accessibility and transcription. As a putative tumor suppressor in several cancers, PBRM1 protein expression is often abrogated by truncations and deletions. However, ∼33% of PBRM1 mutations in cancer are missense and cluster within its bromodomains...

With the advent of molecular immunohistochemistry and next generation sequencing, Switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex altered tumors have gained recognition recently. SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily B member 1 (SMARCB1) and SMARCA4 are the primary SWI/SNF components altered in several recently described undifferentiated malignancies in head and neck region with predilection for paranasal sinuses in SMARCB1-deficient tumors and nasal cavity in SMARCA4-deficient tumors...