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Mouse RNF138 immunoprecipitation mass spectrography analysis in macrophages

ABSTRACT: As one of the core components of the SWI/SNF complex, SMARCC1 (BAF155, SRG3) plays essential roles in activation of the late inflammatory genes in response to microbial challenge. However, little is known about the mechanism how SMARCC1 regulates the inflammatory innate response. Via functional screening, we identify nuclear E3 ubiquitin ligase RNF138 as a negative regulator in inflammatory innate response, and show that RNF138 interacts with SMARCC1 and mediates its K48-linked polyubiquitination at position Lys643 and proteasomal degradation. As a result, catalytic activity of RNF138 fine-tunes the kinetics of late inflammatory gene transcription by inhibiting chromatin remodeling at SWI/SNF regulated gene loci. The reduced RNF138 and increased SMARCC1 in monocytes of rheumatoid arthritis patients are observed. These results provide mechanistic insight into the interplay among nucleosome remodeling, inflammation and ubiquitylation, and underscore the important role of the E3 ubiquitin ligases in controlling both extent and duration of inflammatory responses.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Macrophage

SUBMITTER: Wei Liu

LAB HEAD: Minghong Jiang

PROVIDER: PXD039333 | Pride | 2023-01-10

REPOSITORIES: Pride

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			Action	DRS
	HFX6_FPEP220079742-1A.pdResult	Other
	HFX6_FPEP220079742-1A.raw	Raw
	HFX6_FPEP220079743-1A.pdResult	Other
	HFX6_FPEP220079743-1A.raw	Raw
	HFX6_FPEP220079744-1A.pdResult	Other

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RNF138 inhibits late inflammatory gene transcription through degradation of SMARCC1 of SWI/SNF complex

Project description:As one of the core components of the SWI/SNF complex, SMARCC1 (SAF155, SRG3) plays essential role in activation of the late inflammatory genes in response to microbial challenge. However, little is known about the mechanisms how SMARCC1 is regulated in innate response. Here, we identify for the first time that nuclear E3 ubiquitin ligase RNF138 acts as a critical negative regulator in inflammatory responses. RNF138 selectively interacts with SMARCC1 and mediates its K48-linked polyubiquitination at position Lys643 and proteasomal degradation. As a result, catalytic activity of RNF138 fine-tunes the kinetics of late inflammatory gene transcription by inhibiting persistent chromatin remodeling at SWI/SNF regulated gene loci. These results provide mechanistic insight into the interplay among nucleosome remodeling, inflammation and ubiquitylation, and underscore the critical role of the E3 ligases in controlling both extent and duration of inflammatory responses.

2023-02-11 | GSE207437 | GEO

RNF138 inhibits late inflammatory gene transcription through degradation of SMARCC1 of SWI/SNF complex

Project description:RNF138 inhibits late inflammatory gene transcription through degradation of SMARCC1 of SWI/SNF complex

| PRJNA855477 | ENA

Loss of the E3 ubiquitin ligases UBR-5 or HECD-1 restores Caenorhabditis elegans development in the absence of SWI/SNF function

Project description:SWItch/Sucrose Non-Fermenting (SWI/SNF) complexes are a family of chromatin remodellers that are conserved across eukaryotes. Mutations in subunits of SWI/SNF cause a multitude of different developmental disorders in humans, most of which have no current treatment options. Here we identify an alanine to valine causing mutation in the SWI/SNF subunit snfc-5 (SMARCB1 in humans) that prevents embryonic lethality in C. elegans nematodes harbouring a loss-of-function mutation in the SWI/SNF subunit swsn-1 (SMARCC1/2 in humans). Furthermore, we found that the combination of this specific mutation in snfc-5 and a loss-of-function mutation in either of the E3 ubiquitin ligases ubr-5 (UBR5 in humans) or hecd-1 (HECTD1 in humans) can restore development to adulthood in swsn-1 loss-of-function mutants that otherwise die as embryos. Using these mutant models, we established a set of 335 genes that are dysregulated in SWI/SNF mutants that arrest their development embryonically but exhibit near wild-type levels of expression in the presence of suppressor mutations that prevent embryonic lethality, suggesting that SWI/SNF promotes development by regulating this specific subset of genes. In addition, we show that SWI/SNF protein levels are reduced in swsn-1; snfc-5 double mutants and partly restored to wild-type levels in swsn-1; snfc-5; ubr-5 triple mutants, consistent with a model in which UBR-5 regulates SWI/SNF levels by tagging the complex for proteasomal degradation. Our findings establish a link between two E3 ubiquitin ligases and SWI/SNF function and suggest that UBR5 and HECTD1 might be viable therapeutic targets for the many developmental disorders caused by missense mutations in SWI/SNF subunits.

2023-01-24 | PXD037497 | Pride

Ubiquitinome of G401 SMARCB1-deficient rhabdoid tumor cells

Project description:In this study, DCAF5, a substrate receptor that has been shown to modulate the levels of SWI/SNF subunits, which are components of a chromatin remodeling complex. Here we preformed ubiquitinome proteomics to discover the underlying response of DCAF5 loss on ubiquitylation of SWI/SNF subunits. Furthermore, we determine what sites on SWI/SNF components decrease in ubiquitylation upon DCAF5 loss.

2024-03-25 | PXD046463 | Pride

BRD9 defines a novel SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors [ChIP-seq]

Project description:Bromodomain-containing protein 9 (BRD9) was recently identified to be associated with the chromatin remodeling SWI/SNF(BAF) complex, yet its function within the complex has remained unclear. Here, using genome-scale CRISPR-Cas9 screens, we found that BRD9 constitutes a specific vulnerability in highly malignant pediatric rhabdoid tumors, which are driven by inactivating mutations of SMARCB1 subunit of SWI/SNF complexes. Surprisingly, we found that BRD9 does not belong to the previously identified BAF or PBAF complexes, but instead is found exclusively in a novel of SWI/SNF sub-complex. We show that BRD9-containing complexes lack SMARCB1, which had previously been considered a core subunit present in all SWI/SNF variants. We recently demonstrated that both SMARCB1-containing and ARID1A-containing SWI/SNF complexes preferentially function at enhancers, but here we show that BRD9-containing complexes are located at active promoters as well as enhancers. We show that loss of SMARCB1, as observed in rhabdoid tumors, results in increased BRD9 interaction with SWI/SNF core subunit SMARCC1, consistent with competition between SMARCB1 and BRD9 in the formation of SWI/SNF complexes. Underlying the dependency, we demonstrate that BRD9, via its DUF3512 domain, is essential for maintaining the integrity of its sub-complex, which predominates in the absence of SMARCB1. Taken together, our results reveal a BRD9-containing SWI/SNF subcomplex which is required for the survival of SMARCB1-mutant rhabdoid tumors.

2019-03-14 | GSE120234 | GEO

BRD9 defines a novel SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors [RNA-seq]

2019-03-14 | GSE120233 | GEO

BRD9 defines a novel SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors [RNA-seq 2]

2019-03-14 | GSE125775 | GEO

siRNA Knockdown of SWI/SNF complex proteins in prostate cancer cell lines

Project description:Here we performed transcriptional profiling of the prostate cancer cell lines LNCaP and 22Rv1 comparing non-targeting siRNA treatment versus siRNAs targeting SWI/SNF complex proteins (SMARCA2, SMARCA4, and SMARCB1). Goal was to determine the effect of SWI/SNF knockdown on gene expression in prostate cancer. Two-condition experiment: non-targeting siRNA versus SWI/SNF-siRNA treated cells. Three SWI/SNF proteins were targeted: SMARCA2, SMARCA4, and SMARB1. Biological replicates: 1 control replicate, 2 treatment replicates per SWI/SNF protein. Technical replicates: 1 replicate per SWI/SNF protein. Cell lines: 22Rv1 and LNCaP.

2013-07-20 | E-GEOD-40384 | biostudies-arrayexpress

IPMK physically binds to the SWI/SNF complex and modulates BRG1 occupancy

Project description:Inositol polyphosphate multikinase (IPMK), a key enzyme in the inositol polyphosphate (IP) metabolism, is a pleiotropic signaling factor involved in major biological events, including transcriptional control. In the yeast, IPMK and its IP products promote the activity of the chromatin-remodeling complex SWI/SNF, which plays a critical role in gene expression by regulating chromatin accessibility. However, the direct link between IPMK and chromatin remodelers remains unclear, raising a question on how IPMK contributes to the transcriptional regulation in mammals. By employing unbiased screening approaches and in vivo/in vitro immunoprecipitations, here we demonstrated that mammalian IPMK physically interacts with the SWI/SNF complex by directly binding to SMARCB1, BRG1, and SMARCC1. Furthermore, we identified the specific domains required for the IPMK-SMARCB1 binding. Notably, using the CUT&RUN and ATAC-seq assays, we discovered that IPMK co-localizes with BRG1 and regulates BRG1 localization as well as BRG1-mediated chromatin accessibility in a genome-wide manner in mouse embryonic stem cells. Finally, our mRNA-seq analyses revealed that IPMK and SMARCB1 regulate the expression of a common gene set, validating a functional link between IPMK and the SWI/SNF complex. Together, these findings show that IPMK regulates promoter-targeting of the SWI/SNF complex and thereby contributes to SWI/SNF-meditated chromatin accessibility, transcription, and differentiation.

2022-05-10 | GSE158525 | GEO

Genome-wide profile of the SWI/SNF chromatin remodeling complex

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. 5M-bM-^@M-^Y ends, RNA Polymerases II and III and enhancers) as well as regions critical for chromosome organization (e.g. CTCF, lamins and DNA replication origins). 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. ChIP-Seq analysis of the SWI/SNF subunits Ini1, Brg1, BAF155 and BAF170 in HeLa S3 cells

2011-01-10 | E-GEOD-24397 | biostudies-arrayexpress

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