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The ATP-dependent chromatin remodelling complex BAF (= mammalian SWI/SNF complex) is crucial for the regulation of gene expression and differentiation. In the course of evolution from yeast to mammals, the BAF complex evolved an immense complexity with a high number of subunits encoded by gene families. In this way, tissue-specific BAF function and regulation of development begin with the combinatorial assembly of distinct BAF complexes such as esBAF, npBAF and nBAF. Furthermore, whole-genome sequencing reveals the tremendous role BAF complex mutations have in both neurodevelopmental disorders and human malignancies. Therefore, gaining a more elaborate insight into how BAF complex assembly influences its function and which role distinct subunits play, will hopefully give rise to a better understanding of disease pathogenesis and ultimately to new treatments for many human diseases.

SWI/SNF protein complexes are evolutionarily conserved epigenetic regulators described in all eukaryotes. In metameric animals, the complexes are involved in all processes occurring in the nervous system, from neurogenesis to higher brain functions. On the one hand, the range of roles is wide because the SWI/SNF complexes act universally by mobilizing the nucleosomes in a chromatin template at multiple loci throughout the genome. On the other hand, the complexes mediate the action of multiple signaling pathways that control most aspects of neural tissue development and function. The issues are discussed to provide insight into the molecular basis of the multifaceted role of SWI/SNFs in cell cycle regulation, DNA repair, activation of immediate-early genes, neurogenesis, and brain and connectome formation. An overview is additionally provided for the molecular basis of nervous system pathologies associated with the SWI/SNF complexes and their contribution to neuroinflammation and neurodegeneration. Finally, we discuss the idea that SWI/SNFs act as an integration platform to connect multiple signaling and genetic programs. Graphical Abstract

Background The SWI/SNF complex is an important chromatin remodeler, commonly dysregulated in cancer, with an estimated mutation frequency of 20%. ARID1A is the most frequently mutated subunit gene. Almost nothing is known about the other familiar members of the SWI/SNF complexes, SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1), in oesophageal adenocarcinoma (EAC). Methods We analysed a large cohort of 685 patients with EAC. We used four different antibodies to detect a loss-of-protein of ARID1A BRM, BRG1 and INI1 by immunohistochemistry and correlated these findings with molecular and clinical data. Results Loss of ARID1A, BRG1, BRM and INI1 was observed in 10.4, 3.4, 9.9 and 2% of EAC. We found a co-existing protein loss of ARID1A and BRM in 9.9% and of ARID1A and BRG1 in 2.2%. Patients with loss of ARID1A and TP53 wildtype EACs showed a shortened overall survival compared with AIRDA1A-positive tumours [median overall survival was 60.1 months (95%CI 1.2–139.9 months)] in patients with ARIDA-1A expression and 26.2 months (95%CI 3.7–19.1 months) in cases of ARIDA-1A loss ( p  = 0.044). Tumours with loss or expression of ARID1A and TP53 loss were not associated with a difference in survival. Only one tumour revealed high microsatellite instability (MSI-H) with concomitant ARID1A loss. All other ARID1A loss-EACs were microsatellite-stable (MSS). No predictive relevance was seen for SWI/SNF-complex alterations and simultaneous amplification of different genes (PIK3CA, KRAS, c-MYC, MET, GATA6, ERBB2). Conclusion Our work describes, for the first time, loss of one of the SWI/SNF ATPase subunit proteins in a large number of adenocarcinomas of the oesophagus. Several papers discuss possible therapeutic interventions for tumours showing a loss of function of the SWI/SNF complex, such as PARP inhibitors or PI3K and AKT inhibitors. Future studies will be needed to show whether SWI/SNF complex-deficient EACs may benefit from personalized therapy.

Main conclusionThis study reveals that mutations in BRIP1/2 subunits of the BAS complex disrupt root meristem development by decreasing PIN genes expression, affecting auxin transport, and downregulating essential root genes PLT.Switch defective/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes play vital roles in plant development. BRAHMA-interacting proteins1 (BRIP1) and BRIP2 are subunits of BRAHMA (BRM)-associated SWI/SNF complex (BAS) in plants; however, their role and underlying regulatory mechanism in root development are still unknown. Here, we show that brip1 brip2 double mutants have a significantly shortened root meristem and an irregular arrangement in a portion of the root stem cell niche. The mutations in BRIP1 and BRIP2 cause decreased expression of the PIN-FORMED (PIN) genes, which in turn reduces the transport of auxin at the root tip, leading to the disruption of the accurate establishment of normal auxin concentration gradients in the stem cells. Chromatin immunoprecipitation (ChIP) experiments indicated that BRIP1 and BRIP2 directly bind to the PINs. Furthermore, we found a significant down-regulation in the expression of key root development genes, PLETHORA (PLT), in brip1 brip2. The brip1 brip2 plt1 plt2 quadruple mutations do not show further exacerbation in the short-root phenotype compared to plt1 plt2 double mutants. Using a dexamethasone (DEX)-inducible PLT2 transgenic line, we showed that acute overexpression of PLT2 partially rescues root meristem defects of brip1 brip2, suggesting that BRIP1 and BRIP2 act in part through the PLT1/2 pathway. Taken together, our results identify the critical role and the underlying mechanism of BRIP1/2 in maintaining the development of root meristem through the regulation of auxin output and expression of PLTs.

Background Genes related to the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex are frequently mutated across cancers. SWI/SNF-mutant tumors are vulnerable to synthetic lethal inhibitors. However, the landscape of SWI/SNF mutations and their associations with tumor mutational burden (TMB), microsatellite instability (MSI) status, and response to immune checkpoint inhibitors (ICIs) have not been elucidated in large real-world Chinese patient cohorts. Methods The mutational rates and variation types of six SWI/SNF complex genes ( ARID1A , ARID1B , ARID2 , SMARCA4 , SMARCB1 , and PBRM1 ) were analyzed retrospectively by integrating next-generation sequencing data of 4591 cases covering 18 cancer types. Thereafter, characteristics of SWI/SNF mutations were depicted and the TMB and MSI status and therapeutic effects of ICIs in the SWI/SNF-mutant and SWI/SNF-non-mutant groups were compared. Results SWI/SNF mutations were observed in 21.8% of tumors. Endometrial (54.1%), gallbladder and biliary tract (43.4%), and gastric (33.9%) cancers exhibited remarkably higher SWI/SNF mutational rates than other malignancies. Further, ARID1A was the most frequently mutated SWI/SNF gene, and ARID1A D1850fs was identified as relatively crucial. The TMB value, TMB-high (TMB-H), and MSI-high (MSI-H) proportions corresponding to SWI/SNF-mutant cancers were significantly higher than those corresponding to SWI/SNF-non-mutant cancers (25.8 vs. 5.6 mutations/Mb, 44.3% vs. 10.3%, and 16.0% vs. 0.9%, respectively; all p  < 0.0001). Furthermore, these indices were even higher for tumors with co-mutations of SWI/SNF genes and MLL2/3 . Regarding immunotherapeutic effects, patients with SWI/SNF variations showed significantly longer progression-free survival (PFS) rates than their SWI/SNF-non-mutant counterparts (hazard ratio [HR], 0.56 [95% confidence interval {CI} 0.44–0.72]; p < 0.0001), and PBRM1 mutations were associated with relatively better ICI treatment outcomes than the other SWI/SNF gene mutations (HR, 0.21 [95% CI 0.12–0.37]; p  = 0.0007). Additionally, patients in the SWI/SNF-mutant + TMB-H (HR, 0.48 [95% CI 0.37–0.54]; p  < 0.0001) cohorts had longer PFS rates than those in the SWI/SNF-non-mutant + TMB-low cohort. Conclusions SWI/SNF complex genes are frequently mutated and are closely associated with TMB-H status, MSI-H status, and superior ICI treatment response in several cancers, such as colorectal cancer, gastric cancer, and non-small cell lung cancer. These findings emphasize the necessity and importance of molecular-level detection and interpretation of SWI/SNF complex mutations.

The Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex comprises 10-15 subunits, which modulate the arrangement, location, or conformation of nucleosomes to upregulate chromatin accessibility. During lymphocytic differentiation and functional development, the SWI/SNF complex exerts its effects by binding to specific transcription factors (TFs) or DNA sequences via its subunits, which are thereafter recruited to the promoter or enhancer regions of target genes, rendering each subunit crucial wherein. The loss of individual subunits during lymphocytic differentiation not only disrupts the targeting of the SWI/SNF complex but also impairs its chromatin remodeling function, ultimately resulting in altered differentiation of immature lymphocytes, dysfunction of mature lymphocytes, and injured immune responses. Therefore, in this paper, we focus on TFs interacting with SWI/SNF complex subunits in lymphocytes, and summarize the effects of the loss of specific subunits of the SWI/SNF complex on lymphocytic differentiation and function, as well as the modification in the expression of key genes. We also summarize the potential clinical treatments and applications targeting the loss of SWI/SNF complex subunits, and focus on the application in Chimeric Antigen Receptor (CAR) technology. In conclusion, the SWI/SNF complex is a key regulatory factor in lymphocytic biology, involved in fundamental cellular processes and closely associated with hematological diseases and immune dysfunction. However, the specific roles of SWI/SNF complex subunits in different lymphocytic subpopulations remain unclear. Future clarification of the specific functions of these subunits in different lymphocytic subsets is expected to promote the development of immunotherapy and personalized therapy.

Background/Aim: Recently, inactivating somatic mutations of SWI/SNF chromatin-remodeling genes in cancers have been reported. However, few studies have been performed regarding the immunological analysis of the tumor microenvironment (TME) in chromatin remodeling complex gene-mutated tumors. In the present study, we identified cancer patients harboring various mammalian SWI/SNF complex mutations and investigated the immunological features in those mutated cancers. Patients and Methods: Cancer patients harboring any type of chromatin remodeling complex gene mutation were selected and clinicopathological features were compared between chromatin remodeling complex gene expression-low and expression-high groups. Specifically, expression levels of immune response-associated genes and cancer-associated genes were compared between the SMARCA4 expression-low and expression-high groups using volcano plot analysis. Results: Among cancers harboring PBRM1, SAMRACA4 and ARID2 gene mutations, T-cell marker and mature B-cell marker genes were up-regulated in the tumor. Specifically, T-cell effector genes (CD8B, CD40LG), central memory marker genes (CD27, CCR7) and mature B-cell marker genes (CD20, CD38, CD79 and IRF4) were up-regulated, and cancer-associated genes including MYB, MYC and AURKB genes were down-regulated in the SMARCA4 expression-low group. Remarkably, heatmap of gene expression and immunohistochemistry (IHC) data demonstrated that the tertiary lymphoid structure (TLS) gene signature of mature B cells was up-regulated in SMACA4 gene-mutated stomach cancers. Conclusion: These results suggest that immune tumor microenvironment status, such as mature B cell recruitment featuring the TLS gene signature and immune activation mediated by cancer signal down-regulation, might contribute to the classification of SMARCA4 gene-mutated tumors as immune checkpoint blockade therapy-sensitive target tumors.

Germ cell tumors (GCTs) are the most common solid malignancies found in young men. Although they generally have high cure rates, metastases, resistance to cisplatin-based therapy, and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In a previous study, we identified downregulation of the chromatin-remodeling SWI/SNF complex member ARID1A as a key event in the mode of action of the histone deacetylase inhibitor romidepsin. Additionally, the loss-of-function mutations re-sensitize different tumor types to various drugs, like EZH2-, PARP-, HDAC-, HSP90- or ATR-inhibitors. Thus, ARID1A presents as a promising target for synthetic lethality and combination therapy. In this study, we deciphered the molecular function of ARID1A and screened for the potential of two pharmacological ARID1A inhibitors as a new therapeutic strategy to treat GCTs. By CRISPR/Cas9, we generated ARID1A-deficient GCT cells and demonstrate by mass spectrometry that ARID1A is putatively involved in regulating transcription, DNA repair and the epigenetic landscape via DNA Polymerase POLE and the DNA methyltransferase 1-associated protein DMAP1. Additionally, ARID1A/ARID1A deficiency or pharmacological inhibition increased the efficacy of romidepsin and considerably sensitized GCT cells, including cisplatin-resistant subclones, towards ATR inhibition. Thus, targeting ARID1A in combination with romidepsin and ATR inhibitors presents as a new putative option to treat GCTs.

Cholangiocarcinoma (CCA) is an aggressive malignancy with a 5-year-survival rate of <10%, mainly due to diagnosis in advanced stages and limited therapeutic options in case of progressive disease. Recently, evidence has indicated that alterations in the SWI/SNF-complex (SWI/SNF) may have an important role in the tumorigenesis of CCA. SWI/SNF-related chromatin remodeling has been reported to be crucial for differentiation and tumor suppression, and loss-of-function mutations of SWI/SNF are present in 20% of human malignancies; however, at present, little is known about its relevance in CCA. In the present study, a cohort of 52 patients with the diagnosis of primary CCA was retrospectively collected. All patients underwent surgery with curative intent. Tissue microarray analysis was performed on each tumor for immunohistochemical loss-of-protein analysis of the SWI/SNF core subunits ARID1A, INI-1, BRG1, PBRM-1 and BRM, corresponding to the following CCA subtypes: Extrahepatic CCA (ECCA), small duct or large duct intrahepatic CCA (ICCA). Kaplan-Meier analysis was used to determine survival distribution and survival differences were evaluated by log-rank test. In total, 14 of 52 patients (~35%) exhibited protein-loss of any tested SWI/SNF core subunit. Notably, 17% of patients exhibited a loss of ARID1a; this was the protein loss with the highest frequency. Patients with small and large duct ICCA with protein-loss of any tested SWI/SNF subunit exhibited significantly worse survival compared with the wild-type cohort with proficient protein expression (P=0.013 and P=0.002), whereas no significant survival difference was detected for patients with ECCA. SWI/SNF and its core subunits may be considered promising predictive and therapeutic targets, and require further investigation in patients with CCA.

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42–67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69–100% of SCCOHT cases and SMARCA2 silencing seen 86–100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade.