The Evolutionary Conserved SWI/SNF Subunits ARID1A and ARID1B Are Key Modulators of Pluripotency and Cell-Fate Determination
04 Mar 2021-Frontiers in Cell and Developmental Biology (Front Cell Dev Biol)-Vol. 9, pp 643361-643361
TL;DR: A recent mini-review as mentioned in this paper discusses the available scientific literature linking ARID1A and ARID 1B to cell fate determination, pluripotency maintenance, and organismal development.
Abstract: Organismal development is a process that requires a fine-tuned control of cell fate and identity, through timely regulation of lineage-specific genes. These processes are mediated by the concerted action of transcription factors and protein complexes that orchestrate the interaction between cis-regulatory elements (enhancers, promoters) and RNA Polymerase II to elicit transcription. A proper understanding of these dynamics is essential to elucidate the mechanisms underlying developmental diseases. Many developmental disorders, such as Coffin-Siris Syndrome, characterized by growth impairment and intellectual disability are associated with mutations in subunits of the SWI/SNF chromatin remodeler complex, which is an essential regulator of transcription. ARID1B and its paralog ARID1A encode for the two largest, mutually exclusive, subunits of the complex. Mutations in ARID1A and, especially, ARID1B are recurrently associated with a very wide array of developmental disorders, suggesting that these two SWI/SNF subunits play an important role in cell fate decision. In this mini-review we therefore discuss the available scientific literature linking ARID1A and ARID1B to cell fate determination, pluripotency maintenance, and organismal development.
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TL;DR: The aim of this review was to identify and summarise the currently established biomolecular and genetic prognostic factors that can facilitate decision making for FST in ES-EC and to make more confident decisions on FST on the basis of these factors.
Abstract: Endometrial cancer occurs in up to 29% of women before 40 years of age. Seventy percent of these patients are nulliparous at the time. Decision making regarding fertility preservation in early stage endometrial cancer (ES-EC) is, therefore, a big challenge since the decision between the risk of cancer progression and a chance to parenthood needs to be made. Sixty-two percent of women with complete remission of ES-EC after fertility-sparing treatment (FST) report to have a pregnancy wish which, if not for FST, they would not be able to fulfil. The aim of this review was to identify and summarise the currently established biomolecular and genetic prognostic factors that can facilitate decision making for FST in ES-EC. A comprehensive search strategy was carried out across four databases; Cochrane, Embase, MEDLINE, and PubMed; they were searched between March 1946 and 22nd December 2022. Thirty-four studies were included in this study which was conducted in line with the PRISMA criteria checklist. The final 34 articles encompassed 9165 patients. The studies were assessed using the Critical Appraisal Skills Program (CASP). PTEN and POLE alterations we found to be good prognostic factors of ES-EC, favouring FST. MSI, CTNNB1, and K-RAS alterations were found to be fair prognostic factors of ES-EC, favouring FST but carrying a risk of recurrence. PIK3CA, HER2, ARID1A, P53, L1CAM, and FGFR2 were found to be poor prognostic factors of ES-EC and therefore do not favour FST. Clinical trials with bigger cohorts are needed to further validate the fair genetic prognostic factors. Using the aforementioned good and poor genetic prognostic factors, we can make more confident decisions on FST in ES-EC.
31 citations
TL;DR: In this paper, the authors reviewed recent progress in understanding the composition, assembly, structure, and function of BAF complexes and the consequences of their disease-associated mutations, highlighting intra-complex subunit dependencies and synthetic lethal interactions.
Abstract: BAF complexes are multi-subunit chromatin remodelers, which have a fundamental role in genomic regulation. Large-scale sequencing efforts have revealed frequent BAF complex mutations in many human diseases, particularly in cancer and neurological disorders. These findings not only underscore the importance of the BAF chromatin remodelers in cellular physiological processes, but urge a more detailed understanding of their structure and molecular action to enable the development of targeted therapeutic approaches for diseases with BAF complex alterations. Here, we review recent progress in understanding the composition, assembly, structure, and function of BAF complexes, and the consequences of their disease-associated mutations. Furthermore, we highlight intra-complex subunit dependencies and synthetic lethal interactions, which have emerged as promising treatment modalities for BAF-related diseases.
10 citations
TL;DR: In this paper, the authors leveraged ARID1B+/− Coffin-Siris patient-derived iPSCs and modeled cranial neural crest cell (CNCC) formation.
Abstract: Subunit switches in the BAF chromatin remodeler are essential during development. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause neurodevelopmental disorders, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we leveraged ARID1B+/− Coffin-Siris patient-derived iPSCs and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF). ARID1B-BAF regulates exit from pluripotency and lineage commitment by attenuating thousands of enhancers and genes of the NANOG and SOX2 networks. In iPSCs, these enhancers are maintained active by ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A- to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at the pluripotency enhancers throughout all stages of CNCC formation. This leads to persistent NANOG/SOX2 activity which impairs CNCC formation. Despite showing the typical neural crest signature (TFAP2A/SOX9-positive), ARID1B-haploinsufficient CNCCs are also aberrantly NANOG-positive. These findings suggest a connection between ARID1B mutations, neuroectoderm specification and a pathogenic mechanism for Coffin-Siris syndrome. Mutations in the ARID1B subunit of the BAF chromatin remodeling complex are associated with the neurodevelopmental Coffin-Siris syndrome. Here the authors reveal that there is a transition from ARID1A-containing complexes to ARID1B during cranial neural crest cell differentiation that is impaired in Coffin-Siris patient-derived cells, which is important for exit from pluripotency.
8 citations
TL;DR: A novel BAF configuration is discovered, which includes ARID1B, SMARCA4, and eight additional subunits, which acts as a gate-keeper which ensures exit from pluripotency and commitment towards neural crest differentiation, by attenuating pluripOTency enhancers of the SOX2 network.
Abstract: The BAF complex modulates genome-wide chromatin accessibility Specific BAF configurations have been shown to have functional consequences, and subunit switches are essential for cell differentiation ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits De novo ARID1B haploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features Here, we reprogrammed ARID1B+/- Coffin-Siris patient-derived skin fibroblasts into iPSCs, and investigated cranial neural crest cell (CNCC) differentiation We discovered a novel BAF configuration (ARID1B-BAF), which includes ARID1B, SMARCA4, and eight additional subunits This novel version of BAF acts as a gate-keeper which ensures exit from pluripotency and commitment towards neural crest differentiation, by attenuating pluripotency enhancers of the SOX2 network At the iPSC stage, these enhancers are maintained in active state by an ARID1A-containing BAF At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of SOX2 enhancers and pluripotency exit Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout CNCC differentiation This correlates with aberrant SOX2 binding at pluripotency enhancers, and failure to reposition SOX2 at developmental enhancers SOX2 dysregulation promotes upregulation of the NANOG network, impairing CNCC differentiation ARID1B-BAF directly modulates NANOG expression upon differentiation cues Intriguingly, the cells with the most prominent molecular phenotype in multiple experimental assays are derived from a patient with a more severe clinical impairment These findings suggest a direct connection between ARID1B mutations, CNCC differentiation, and a pathogenic mechanism for Coffin-Siris syndrome
8 citations
TL;DR: In this paper, the authors proposed a series of mechanisms related to the resistance to EGFR-TKIs induced by ARID1A alterations or expression loss and the potential therapeutic strategies to overcome the resistance based on published studies.
Abstract: ARID1A is a key component of the SWI/SNF chromatin remodeling complexes which is important for the maintaining of biological processes of cells. Recent studies had uncovered the potential role of ARID1A alterations or expression loss in the therapeutic sensitivity of cancers, but the studies in this field requires to be further summarized and discussed. Therefore, we proposed a series of mechanisms related to the resistance to EGFR-TKIs induced by ARID1A alterations or expression loss and the potential therapeutic strategies to overcome the resistance based on published studies. It suggested that ARID1A alterations or expression loss might be the regulators in PI3K/Akt, JAK/STAT and NF-κB signaling pathways which are strongly associated with the resistance to EGFR-TKIs in NSCLC patients harboring sensitive EGFR mutations. Besides, ARID1A alterations or expression loss could lead to the resistance to EGFR-TKIs via a variety of processes during the tumorigenesis and development of cancers, including epithelial to mesenchymal transition, angiogenesis and the inhibition of apoptosis. Based on the potential mechanisms related to ARID1A, we summarized that the small molecular inhibitors targeting ARID1A or PI3K/Akt pathway, the anti-angiogenic therapy and immune checkpoint inhibitors could be used for the supplementary treatment for EGFR-TKIs among NSCLC patients harboring the concomitant alterations of sensitive EGFR mutations and ARID1A.
7 citations
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1,063 citations
TL;DR: The brahma (brm) gene encodes a 1638 residue protein that is similar to SNF2/SWI2, a protein involved in transcriptional activation in yeast, suggesting possible models for the role of brm in the transcriptionalactivation of homeotic genes.
951 citations
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Abstract: We have purified distinct complexes of nine to 12 proteins [referred to as BRG1-associated factors (BAFs)] from several mammalian cell lines using an antibody to the SWI2-SNF2 homolog BRG1. Microsequencing revealed that the 47 kDa BAF is identical to INI1. Previously INI1 has been shown to interact with and activate human immunodeficiency virus integrase and to be homologous to the yeast SNF5 gene. A group of BAF47-associated proteins were affinity purified with antibodies against INI1/BAF47 and were found to be identical to those co-purified with BRG1, strongly indicating that this group of proteins associates tightly and is likely to be the mammalian equivalent of the yeast SWI-SNF complex. Complexes containing BRG1 can disrupt nucleosomes and facilitate the binding of GAL4-VP16 to a nucleosomal template similar to the yeast SWI-SNF complex. Purification of the complex from several cell lines demonstrates that it is heterogeneous with respect to subunit composition. The two SWI-SNF2 homologs, BRG1 and hbrm, were found in separate complexes. Certain cell lines completely lack BRG1 and hbrm, indicating that they are not essential for cell viability and that the mammalian SWI-SNF complex may be tailored to the needs of a differentiated cell type.
824 citations
TL;DR: The observed similarity between mammalian BAF190, Baf170, BAF155, B AF60, and BAF47 and yeast SNF2/SWI2, SWI3, SWP73, and SNF5, respectively, underscores the similarity of the mammalian and yeast complexes.
Abstract: The SWI/SNF complex in yeast facilitates the function of transcriptional activators by opposing chromatin-dependent repression of transcription. We demonstrate that in mammals SWI/SNF complexes are present in multiple forms made up of 9-12 proteins that we refer to as BRG1-associated factors (BAFs) ranging from 47 to 250 kD. We have isolated cDNAs for human BAF155, BAF170, and BAF60. BAF155 and BAF170 are encoded by separate genes that are both homologs of yeast SWI3. Both contain a region of similarity to the DNA binding domain of myb, but lack the basic residues known to be necessary for interaction with DNA. The two SWI3 homologs copurify on antibody columns specific for either BAF155 or BAF170, indicating that they are in the same complex. BAF60 is encoded by a novel gene family. An open reading frame from yeast, which is highly homologous, encodes the previously uncharacterized 73-kD subunit of the yeast SWI/SNF complex required for transcriptional activation by the glucocorticoid receptor (Cairns et al., this issue). BAF60a is expressed in all tissues examined, whereas BAF60b and BAF60c are expressed preferentially in muscle and pancreas, respectively. BAF60a is present within the 2000-kD BRG1 complex, whereas BAF60b is in a distinct complex that shares some but not all subunits with the BRG1 complex. The observed similarity between mammalian BAF190, BAF170, BAF155, BAF60, and BAF47 and yeast SNF2/SWI2, SWI3, SWI3, SWP73, and SNF5, respectively, underscores the similarity of the mammalian and yeast complexes. However, the complexes in mammals are more diverse than the SWI/SNF complex in yeast and are likely dedicated to developmentally distinct functions.
695 citations
TL;DR: It is suggested that SWI/SNF-like complexes in vertebrates achieve biological specificity by combinatorial assembly of their subunits by preventing the subunit switch impairs neuronal differentiation.
674 citations