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Project description:Homeobox-B13 (HOXB13) is a master transcriptional regulator which is exclusively expressed in the prostate tissue and has been shown to be crucial for its embryonic development. There is extensive clinical and experimental evidence to support the role of HOXB13 in prostate cancer (PCa). Yet, despite this critical role, the function of HOXB13 remains controversial with some studies supporting an oncogenic role and others demonstrating a tumor-suppressive role. While there is a clear relationship between HOXB13 and AR there are conflicting studies if HOXB13 is itself regulated by AR. Interrogating various AR +ve and AR -ve in-vivo and in-vitro models, in this study, we demonstrate that HOXB13 is crucial for the growth and proliferation of PCa regardless of its androgen dependency. We show that HOXB13 activity in these different models is mediated via interactions with cell-specific transcription factors. Yet despite the diverse transcription factor interactions, HOXB13 activity is commonly modulated by SMARCD2, a member of the mSWI/SNF chromatin remodeling complex. The HOXB13/SMARCD2 interaction is stabilized through interactions with transcription factors. This interaction alters the chromatin accessibility at HOXB13 binding sites which leads to increased proliferation in PCa.
2025-11-18 | GSE228743 | GEO
Project description:Homeobox-B13 (HOXB13) is a master transcriptional regulator which is exclusively expressed in the prostate tissue and has been shown to be crucial for its embryonic development. There is extensive clinical and experimental evidence to support the role of HOXB13 in prostate cancer (PCa). Yet, despite this critical role, the function of HOXB13 remains controversial with some studies supporting an oncogenic role and others demonstrating a tumor-suppressive role. While there is a clear relationship between HOXB13 and AR there are conflicting studies if HOXB13 is itself regulated by AR. Interrogating various AR +ve and AR -ve in-vivo and in-vitro models, in this study, we demonstrate that HOXB13 is crucial for the growth and proliferation of PCa regardless of its androgen dependency. We show that HOXB13 activity in these different models is mediated via interactions with cell-specific transcription factors. Yet despite the diverse transcription factor interactions, HOXB13 activity is commonly modulated by SMARCD2, a member of the mSWI/SNF chromatin remodeling complex. The HOXB13/SMARCD2 interaction is stabilized through interactions with transcription factors. This interaction alters the chromatin accessibility at HOXB13 binding sites which leads to increased proliferation in PCa.
2025-11-18 | GSE228742 | GEO
Project description:HOXB13 alters chromatin accessibility in prostate cancer through interactions with the SWI/SNF complex
| PRJNA951385 | ENA
Project description:Notch signaling plays a key role in many cell fate decisions during development by directing different gene expression programs via the transcription factor CSL, known as Su(H) in Drosophila Which target genes are responsive to Notch signaling is influenced by the chromatin state of enhancers, yet how this is regulated is not fully known. Detecting a specific increase in the histone variant H3.3 in response to Notch signaling, we tested which chromatin remodelers or histone chaperones are required for the changes in enhancer accessibility to Su(H) binding. We show a crucial role for the Brahma SWI/SNF chromatin remodeling complex, including the actin-related BAP55 subunit, in conferring enhancer accessibility and enabling the transcriptional response to Notch activity. The Notch-responsive regions have high levels of nucleosome turnover which depend on the Brahma complex, increase in magnitude with Notch signaling, and primarily involve histone H3.3. Together these results highlight the importance of SWI/SNF-mediated nucleosome turnover in rendering enhancers responsive to Notch.
| S-EPMC6500979 | biostudies-literature
Project description: Not available
| S-EPMC6251806 | biostudies-literature
Project description:In eukaryotes, ATP-dependent chromatin remodelers regulate gene expression in response to nutritional and metabolic stimuli. However, altered transcription of metabolic genes may have significant indirect consequences which are currently poorly understood. In this study, we use genetic and molecular approaches to uncover a role for the remodeler Swi-Snf as a critical regulator of metabolism. We find that snfΔ mutants display a cysteine-deficient phenotype, despite growth in nutrient-rich media. This correlates with widespread perturbations in sulfur metabolic gene transcription, including global redistribution of the sulfur-sensing transcription factor Met4. Our findings show how a chromatin remodeler can have a significant impact on a whole metabolic pathway by directly regulating an important gene subset and demonstrate an emerging role for chromatin remodeling complexes as decisive factors in metabolic control.
| S-EPMC10602859 | biostudies-literature
Project description:A systems understanding of nuclear organization and events is critical for determining how cells divide, differentiate, and respond to stimuli and for identifying the causes of diseases. Chromatin remodeling complexes such as SWI/SNF have been implicated in a wide variety of cellular processes including gene expression, nuclear organization, centromere function, and chromosomal stability, and mutations in SWI/SNF components have been linked to several types of cancer. To better understand the biological processes in which chromatin remodeling proteins participate, we globally mapped binding regions for several components of the SWI/SNF complex throughout the human genome using ChIP-Seq. SWI/SNF components were found to lie near regulatory elements integral to transcription (e.g. 5' ends, RNA Polymerases II and III, and enhancers) as well as regions critical for chromosome organization (e.g. CTCF, lamins, and DNA replication origins). Interestingly we also find that certain configurations of SWI/SNF subunits are associated with transcripts that have higher levels of expression, whereas other configurations of SWI/SNF factors are associated with transcripts that have lower levels of expression. To further elucidate the association of SWI/SNF subunits with each other as well as with other nuclear proteins, we also analyzed SWI/SNF immunoprecipitated complexes by mass spectrometry. Individual SWI/SNF factors are associated with their own family members, as well as with cellular constituents such as nuclear matrix proteins, key transcription factors, and centromere components, implying a ubiquitous role in gene regulation and nuclear function. We find an overrepresentation of both SWI/SNF-associated regions and proteins in cell cycle and chromosome organization. Taken together the results from our ChIP and immunoprecipitation experiments suggest that SWI/SNF facilitates gene regulation and genome function more broadly and through a greater diversity of interactions than previously appreciated.
| S-EPMC3048368 | biostudies-literature
Project description:The glucocorticoid receptor (GR) is a steroid-hormone-activated transcription factor that modulates gene expression. Transcriptional regulation by the GR requires dynamic receptor binding to specific target sites located across the genome. This binding remodels the chromatin structure to allow interaction with other transcription factors. Thus, chromatin remodeling is an essential component of GR-mediated transcriptional regulation, and understanding the interactions between these molecules at the structural level provides insights into the mechanisms of how GR and chromatin remodeling cooperate to regulate gene expression. This study suggests models for the assembly of the SWI/SNF-A (SWItch/Sucrose-NonFermentable) complex and its interaction with the GR. We used the PRISM algorithm (PRotein Interactions by Structural Matching) to predict the three-dimensional complex structures of the target proteins. The structural models indicate that BAF57 and/or BAF250 mediate the interaction between the GR and the SWI/SNF-A complex, corroborating experimental data. They further suggest that a BAF60a/BAF155 and/or BAF60a/BAF170 interaction is critical for association between the core and variant subunits. Further, we model the interaction between GR and CCAAT-enhancer-binding proteins (C/EBPs), since the GR can regulate gene expression indirectly by interacting with other transcription factors like C/EBPs. We observe that GR can bind to bZip domains of the C/EBPα homodimer as both a monomer and dimer of the DNA-binding domain. In silico mutagenesis of the predicted interface residues confirm the importance of these residues in binding. In vivo analysis of the computationally suggested mutations reveals that double mutations of the leucine residues (L317D+L335D) may disrupt the interaction between GR and C/EBPα. Determination of the complex structures of the GR is of fundamental relevance to understanding its interactions and functions, since the function of a protein or a complex is dictated by its structure. In addition, it may help us estimate the effects of mutations on GR interactions and signaling.
| S-EPMC4576152 | biostudies-literature
Project description:ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancer. Deficiency in its homolog ARID1B is synthetically lethal with ARID1A mutation. However, the functional relationship between these homologs has not been explored. Here, we use ATAC-seq, genome-wide histone modification mapping, and expression analysis to examine colorectal cancer cells lacking one or both ARID proteins. We find that ARID1A has a dominant role in maintaining chromatin accessibility at enhancers, while the contribution of ARID1B is evident only in the context of ARID1A mutation. Changes in accessibility are predictive of changes in expression and correlate with loss of H3K4me and H3K27ac marks, nucleosome spacing, and transcription factor binding, particularly at growth pathway genes including MET. We find that ARID1B knockdown in ARID1A mutant ovarian cancer cells causes similar loss of enhancer architecture, suggesting that this is a conserved function underlying the synthetic lethality between ARID1A and ARID1B.
| S-EPMC5643100 | biostudies-literature
Project description:Switch defective/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes are multi-subunit machineries that establish and maintain chromatin accessibility and gene expression by regulating chromatin structure. However, how the remodeling activities of SWI/SNF complexes are regulated in eukaryotes remains elusive. B-cell lymphoma/leukemia protein 7 A/B/C (BCL7A/B/C) have been reported as subunits of SWI/SNF complexes for decades in animals and recently in plants; however, the role of BCL7 subunits in SWI/SNF function remains undefined. Here, we identify a unique role for plant BCL7A and BCL7B homologous subunits in potentiating the genome-wide chromatin remodeling activities of SWI/SNF complexes in plants. BCL7A/B require the catalytic ATPase BRAHMA (BRM) to assemble with the signature subunits of the BRM-Associated SWI/SNF complexes (BAS) and for genomic binding at a subset of target genes. Loss of BCL7A and BCL7B diminishes BAS-mediated genome-wide chromatin accessibility without changing the stability and genomic targeting of the BAS complex, highlighting the specialized role of BCL7A/B in regulating remodeling activity. We further show that BCL7A/B fine-tune the remodeling activity of BAS complexes to generate accessible chromatin at the juvenility resetting region (JRR) of the microRNAs MIR156A/C for plant juvenile identity maintenance. In summary, our work uncovers the function of previously elusive SWI/SNF subunits in multicellular eukaryotes and provides insights into the mechanisms whereby plants memorize the juvenile identity through SWI/SNF-mediated control of chromatin accessibility.
| S-EPMC10830565 | biostudies-literature