SWI/SNF: The crossroads where extracellular signaling pathways meet chromatin

Simone, Cristiano

doi:10.1002/jcp.20514

Cited by 91 publications

(84 citation statements)

References 64 publications

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“…Because BAF47 is a core subunit of BAF complexes (22,40) and a previous study reported that siRNA-mediated inhibition of BAF47 prevented IFN-␤ induction in HeLa cells (41), we measured BAF47 binding to nucleosomes 1 and 2 in tolerant cells before and after RelB knockdown. As shown in Fig.…”

Section: Baf Chromatin-remodeling Complex Is Required For Nucleosome mentioning

confidence: 99%

Dynamic and Selective Nucleosome Repositioning during Endotoxin Tolerance

Gazzar

Liu

Yoza

et al. 2010

Journal of Biological Chemistry

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Sepsis is encoded by a sequel of transcription activation and repression events that initiate, sustain, and resolve severe systemic inflammation. The repression/silencing phase occurs in blood leukocytes of animals and humans following the initiation of systemic inflammation due to developing endotoxin tolerance. We previously reported that NF-B transcription factor RelB and histone H3 lysine methyltransferase G9a directly interact to induce facultative heterochromatin assembly and regulate epigenetic silencing during endotoxin tolerance, which is a major feature of sepsis. The general objective of this study was to assess whether dynamic temporal, structural, and positional changes of nucleosomes influence the sepsis phenotype. We used the THP-1 sepsis cell model to isolate mononucleosomes by rapid cell permeabilization and digestion of chromatin with micrococcal nuclease and then compared tumor necrosis factor ␣ (TNF␣) proximal promoter nucleosome alignment in endotoxin-responsive and -tolerant phenotypes. We found differential and dynamic repositioning of nucleosomes from permissive to repressive locations during the activation and silencing phases of transcription reprogramming and identified the following mechanisms that may participate in the process. 1) Two proximal nucleosomes repositioned to expose the primary NF-B DNA binding site in endotoxin-responsive cells, and this "promoter opening" required the ATP-independent chaperone NAP1 to replace the core histone H2A with the H2A.Z variant. 2) During RelB-dependent endotoxin tolerance, the two nucleosomes repositioned and masked the primary NF-B DNA binding site. 3) Small interfering RNA-mediated inhibition of RelB expression prevented repressive nucleosome repositioning and tolerance induction, but the "open" promoter required endotoxin-induced NF-B p65 promoter binding to initiate transcription, supporting the known requirement of p65 posttranslational modifications for transactivation. 4) Sustaining the permissive promoter state after RelB knockdown required ATP-dependent nucleosome remodeler BAF complex. Moreover, we found that forced expression of RelB in responsive cells induced repressive nucleosome positioning and silenced TNF␣ transcription, demonstrating the plasticity of nucleosome remodeling and its dependence on RelB. Our data suggest that nucleosome repositioning controls both the induction and epigenetic silencing phases of TNF␣ transcription associated with sepsis.

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Section: Baf Chromatin-remodeling Complex Is Required For Nucleosome mentioning

confidence: 99%

Dynamic and Selective Nucleosome Repositioning during Endotoxin Tolerance

Gazzar

Liu

Yoza

et al. 2010

Journal of Biological Chemistry

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“…Our research and that of others has shown that BRG1-and BRM-deficient cell lines are resistant to Rbmediated growth inhibition, and that reexpressing BRM in these cells is sufficient to restore Rb-mediated growth inhibition Strobeck et al, 2002). The SWI/SNF complex and BRM are also required for differentiation and development (Simone, 2006). Loss of BRM has also been shown to impact cell migration and metastasis (Yamamichi et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

et al. 2007

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The SWI/SNF chromatin-remodeling complex serves as a master switch that directs and limits the execution of specific cellular programs, such as differentiation and growth control. SWI/SNF function requires one of two paralogous ATPase subunits, Brahma (BRM) or BRMrelated gene 1 (BRG1), which we previously found are lost together in cancer cell lines and primary lung cancers. Although BRG1 has been found to be mutated in cancer cell lines, the mechanisms underlying BRM silencing are not known. To address this question, we sequenced BRM in 10 BRM/BRG1-deficient cancer cell lines and found that BRM was devoid of abrogating mutations. Moreover, histone deacetylase (HDAC) inhibitors restored BRM expression in each of these BRG1/BRM-deficient cancer cell lines, indicating that epigenetic silencing is a major mechanism underlying the loss of BRM expression. Despite their ability to restore BRM expression, these HDAC inhibitors also blocked BRM function when present. However, after their removal, we observed that BRM expression remained elevated for several days, and during this period, BRM activity was detected. We also found that the suppression of BRM occurs in a broad range of human tumor types and that loss of one or both BRM alleles potentiated tumor development in mice. Thus, BRG1 and BRM are silenced by different mechanisms, and it may be possible to clinically target and reexpress BRM in a number of tumor types, potentially impacting tumor development.

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“…10 This mechanism resembles that described for p38a/b in muscle cells, where they phosphorylate the transcription factor MEF2 and the SWI/SNF subunit BAF60 to remodel chromatin and activate tissue-specific transcription. 11,12 Interestingly, chromatin remodeling complex dysfunction has been described in human colorectal cancer cells. 13 The p38 pathway is often activated by stressful stimuli and cytokines leading to diverse cell type-specific responses, such as cell survival or apoptosis.…”

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confidence: 99%

A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells

et al. 2006

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Cancer develops when molecular pathways that control the fine balance between proliferation, differentiation, autophagy and cell death undergo genetic deregulation. The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of these pathways in tumor cells. In an effort to evaluate the impact of p38 signaling on colorectal cancer cell fate, we treated HT29, Caco2, Hct116, LS174T and SW480 cell lines with the inhibitor SB202190 specific for p38a/b kinases. We report that p38a is required for colorectal cancer cell homeostasis as the inhibition of its kinase function by pharmacological blockade or genetic inactivation causes cell cycle arrest, autophagy and cell death in a cell type-specific manner. Deficiency of p38a activity induces a tissue-restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis. These data identify p38a as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38a pathway in the treatment of colorectal cancer. Colorectal cancer is a major health concern, with more than 1 000 000 new cases and 500 000 deaths expected worldwide per year.1 Prognostic evaluation is currently based on histological appearance, and there are no molecular markers internationally recognized as standard predictor factors. The conventional therapy involving surgery and adjuvant therapy seems to give rise to improvements in progression-free and overall survival. Nevertheless about 50% of patients die within 5 years owing to metastasis or recurrent disease.2 The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of cell cycle and cell death regulatory pathways in tumor cells in order to identify differential cellular effects of agents that may have a direct impact on cancer therapy.During the last decade, a number of deacetylase inhibitors (DI) have been identified. These DI induce tumor cells to undergo growth arrest, differentiation, and/or apoptosis in culture and in animal models, at doses that seem to be nontoxic and appear to be selective. Butyrate, a DI that is naturally formed in the human colon, is able to reduce the size and the number of tumors in rat models of bowel cancer.3 In vitro, sodium butyrate (NaB) is a potent differentiating agent for several colorectal cancer cell lines (CRCs).4-6 NaB-mediated cell cycle withdrawal of CRCs appears to be dependent on acetylation of histones and consequent changes in transcription, requiring continuous protein synthesis and the expression of p21. 7 It has recently been shown that 1 mM NaB is the best working concentration to activate the differentiation program in CRCs without triggering apoptosis, whereas 5 mM NaB is sufficient to induce a p53-independent...

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SWI/SNF: The crossroads where extracellular signaling pathways meet chromatin

Cited by 91 publications

References 64 publications

Dynamic and Selective Nucleosome Repositioning during Endotoxin Tolerance

Dynamic and Selective Nucleosome Repositioning during Endotoxin Tolerance

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells

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