scholarly journals ARID1A loss in neuroblastoma promotes the adrenergic-to-mesenchymal transition by regulating enhancer-mediated gene expression

2020 ◽  
Vol 6 (29) ◽  
pp. eaaz3440 ◽  
Author(s):  
Hui Shi ◽  
Ting Tao ◽  
Brian J. Abraham ◽  
Adam D. Durbin ◽  
Mark W. Zimmerman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Neuroblastoma Cells ◽  
Tumor Development ◽  
Mesenchymal Cell ◽  
Drug Resistant ◽  
Zebrafish Model ◽  
Mesenchymal Transition ◽  
Genes Encoding ◽  
Chromatin Remodeling Complexes

Mutations in genes encoding SWI/SNF chromatin remodeling complexes are found in approximately 20% of all human cancers, with ARID1A being the most frequently mutated subunit. Here, we show that disruption of ARID1A homologs in a zebrafish model accelerates the onset and increases the penetrance of MYCN-driven neuroblastoma by increasing cell proliferation in the sympathoadrenal lineage. Depletion of ARID1A in human NGP neuroblastoma cells promoted the adrenergic-to-mesenchymal transition with changes in enhancer-mediated gene expression due to alterations in the genomic occupancies of distinct SWI/SNF assemblies, BAF and PBAF. Our findings indicate that ARID1A is a haploinsufficient tumor suppressor in MYCN-driven neuroblastoma, whose depletion enhances tumor development and promotes the emergence of the more drug-resistant mesenchymal cell state.

scholarly journals Cardiac enriched BAF chromatin remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function

2017 ◽  
Author(s):  
Xin Sun ◽  
Swetansu K. Hota ◽  
Yu-Qing Zhou ◽  
Stefanie Novak ◽  
Dario Miguel-Perez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Heart Development ◽  
Gene Networks ◽  
Contractile Function ◽  
Conditional Deletion ◽  
Genes Encoding ◽  
Organ Specific ◽  
Chromatin Remodeling Complexes ◽  
And Function

AbstractHow gene networks controlling organ-specific properties are modulated by chromatin remodeling complexes is not well understood. Baf60c (Smarcd3) encodes a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex. Its role throughout heart development is not fully understood. We show that constitutive loss of Baf60c leads to embryonic cardiac hypoplasia and pronounced cardiac dysfunction. Conditional deletion of Baf60c in cardiomyocytes results in postnatal dilated cardiomyopathy with impaired contractile function. Baf60c regulates a gene expression program that includes genes encoding contractile proteins, modulators of sarcomere function, and cardiac metabolic genes. Many of the genes deregulated in Baf60c null embryos are targets of the MEF2/SRF co-factor Myocardin (MYOCD). In a yeast two-hybrid screen we identify MYOCD as a BAF60c interacting factor; we show that BAF60c and MYOCD directly and functionally interact. We conclude that Baf60c is essential for coordinating a program of gene expression that regulates the fundamental functional properties of cardiomyocytes.

scholarly journals Comparative Analysis of SWIRM Domain-Containing Proteins in Plants

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Yan Gao ◽  
Songguang Yang ◽  
Lianyu Yuan ◽  
Yuhai Cui ◽  
Keqiang Wu
Keyword(s):  
Chromatin Remodeling ◽  
Essential Role ◽  
Atp Hydrolysis ◽  
Chromatin Modification ◽  
Dna Binding Proteins ◽  
Plant Responses ◽  
Chromosomal Proteins ◽  
Genes Encoding ◽  
Chromatin Remodeling Complexes ◽  
Affect Gene Expression

Chromatin-remodeling complexes affect gene expression by using the energy of ATP hydrolysis to locally disrupt or alter the association of histones with DNA. SWIRM (Swi3p, Rsc8p, and Moira) domain is an alpha-helical domain of about 85 residues in chromosomal proteins. SWIRM domain-containing proteins make up large multisubunit complexes by interacting with other chromatin modification factors and may have an important function in plants. However, little is known about SWIRM domain-containing proteins in plants. In this study, 67 SWIRM domain-containing proteins from 6 plant species were identified and analyzed. Plant SWIRM domain proteins can be divided into three distinct types: Swi-type, LSD1-type, and Ada2-type. Generally, the SWIRM domain forms a helix-turn-helix motif commonly found in DNA-binding proteins. The genes encoding SWIRM domain proteins inOryza sativaare widely expressed, especially in pistils. In addition,OsCHB701andOsHDMA701were downregulated by cold stress, whereasOsHDMA701andOsHDMA702were significantly induced by heat stress. These observations indicate that SWIRM domain proteins may play an essential role in plant development and plant responses to environmental stress.

scholarly journals Cathepsin B Is Upregulated and Mediates ECM Degradation in Colon Adenocarcinoma HT29 Cells Overexpressing Snail

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 203 ◽  
Author(s):  
Jakub Kryczka ◽  
Izabela Papiewska-Pajak ◽  
M. Anna Kowalska ◽  
Joanna Boncela
Keyword(s):  
Cathepsin B ◽  
Epithelial To Mesenchymal Transition ◽  
Early Stage ◽  
Tumor Development ◽  
Colon Adenocarcinoma ◽  
Mesenchymal Cell ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
Colon And Rectum ◽  
Phenotypic Shift

During tumor development and ongoing metastasis the acquisition of mesenchymal cell traits by epithelial carcinoma cells is achieved through a programmed phenotypic shift called the epithelial-to-mesenchymal transition, EMT. EMT contributes to increased cancer cell motility and invasiveness mainly through invadosomes, the adhesion structures that accompany the mesenchymal migration. The invadosomes and their associated proteases restrict protease activity to areas of the cell in direct contact with the ECM, thus precisely controlling cell invasion. Our data prove that Snail-overexpressing HT-29 cells that imitate the phenotype of colon cancer cells in the early stage of the EMT showed an increase in the expression and pericellular activity of cathepsin B. It appears that the pericellular localization of cathepsin B, also observed in colon and rectum adenocarcinoma tissue samples, plays a key role in its function.

scholarly journals Distinct Cytosine Modification Profiles Define Epithelial-to-Mesenchymal Cell-State Transitions

2021 ◽  
Author(s):  
Min Kyung Lee ◽  
Meredith S. Brown ◽  
Owen Wilkins ◽  
Diwakar R. Pattabiraman ◽  
Brock C. Christensen
Keyword(s):  
Gene Expression ◽  
Cytosine Methylation ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Cell ◽  
State Transitions ◽  
Open Chromatin ◽  
Intermediate Cell ◽  
Mesenchymal Transition ◽  
Accessible Chromatin ◽  
Cytosine Modification

Abstract Background: Epithelial-to-mesenchymal transition (EMT) is an early step in the invasion-metastasis cascade, involving progression through a number of cell intermediate states. Due to challenges with isolating intermediate cell states in EMT, genome-wide cytosine modification mechanisms that define transition through EMT states are not completely understood. We measured multiple DNA cytosine methylation modification marks, complemented with chromatin accessibility and gene expression, across clonal populations residing in specific EMT states. Results: Clones exhibiting intermediate EMT phenotypes demonstrated increased global 5-hydroxymethylcytosine (5hmC), decreased 5-methylcytosine (5mC), and more accesible chromatin. Open chromatin regions containing CpG loci with abundant 5hmC were enriched in motifs of key EMT transcription factors, ZEB1 and Snail. The magnitude of altered gene expression in intermediate cell states was higher for genes both with increased gene promoter 5hmC and differentially accessible chromatin compared with genes that exhibited differentially accessible chromatin alone, implicating functional epigenetic duality in regulation of EMT.Conclusion: Our results indicate the importance of both distinct and shared epigenetic profiles at the cytosine and chromatin level associated with EMT processes that contribute to gene regulation and which may be targeted to prevent the progression of EMT.

scholarly journals The Drosophila SWI/SNF chromatin-remodeling complexes BAP and PBAP play separate roles in regulating growth and cell fate during regeneration

2018 ◽  
Author(s):  
Yuan Tian ◽  
Rachel K. Smith-Bolton
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Chromatin Remodeling ◽  
Tissue Regeneration ◽  
Wing Disc ◽  
Epithelial Tissue ◽  
Growth Promoter ◽  
Jnk Signaling ◽  
Regenerative Growth ◽  
Chromatin Remodeling Complexes

AbstractTo regenerate, damaged tissue must heal the wound, regrow to the proper size, replace the correct cell types, and return to the normal gene-expression program. However, the mechanisms that temporally and spatially control the activation or repression of important genes during regeneration are not fully understood. To determine the role that chromatin modifiers play in regulating gene expression after tissue damage, we induced ablation in Drosophila imaginal wing discs, and screened for chromatin regulators that are required for epithelial tissue regeneration. Here we show that many of these genes are indeed important for promoting or constraining regeneration. Specifically, the two SWI/SNF chromatin-remodeling complexes play distinct roles in regulating different aspects of regeneration. The PBAP complex regulates regenerative growth and developmental timing, and is required for the expression of JNK signaling targets and the growth promoter Myc. By contrast, the BAP complex ensures correct patterning and cell fate by stabilizing expression of the posterior gene engrailed. Thus, both SWI/SNF complexes are essential for proper gene expression during tissue regeneration, but they play distinct roles in regulating growth and cell fate.Summary statementDuring regeneration of the Drosophila wing disc, the SWI/SNF PBAP complex is required for regenerative growth and expression of JNK signaling targets, while the BAP complex maintains posterior cell fate.

scholarly journals FBXO32 links ubiquitination to epigenetic reprograming of melanoma cells

2021 ◽  
Author(s):  
Nadia Habel ◽  
Najla El-Hachem ◽  
Frédéric Soysouvanh ◽  
Hanene Hadhiri-Bzioueche ◽  
Serena Giuliano ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Target Gene ◽  
Tumor Development ◽  
Melanoma Cells ◽  
Complex Activity ◽  
Cellular Processes ◽  
Chromatin Remodeling Complex ◽  
Chromatin Remodeling Complexes ◽  
Proliferation And Invasion

AbstractUbiquitination by serving as a major degradation signal of proteins, but also by controlling protein functioning and localization, plays critical roles in most key cellular processes. Here, we show that MITF, the master transcription factor in melanocytes, controls ubiquitination in melanoma cells. We identified FBXO32, a component of the SCF E3 ligase complex as a new MITF target gene. FBXO32 favors melanoma cell migration, proliferation, and tumor development in vivo. Transcriptomic analysis shows that FBXO32 knockdown induces a global change in melanoma gene expression profile. These include the inhibition of CDK6 in agreement with an inhibition of cell proliferation and invasion upon FBXO32 silencing. Furthermore, proteomic analysis identifies SMARC4, a component of the chromatin remodeling complexes BAF/PBAF, as a FBXO32 partner. FBXO32 and SMARCA4 co-localize at loci regulated by FBXO32, such as CDK6 suggesting that FBXO32 controls transcription through the regulation of chromatin remodeling complex activity. FBXO32 and SMARCA4 are the components of a molecular cascade, linking MITF to epigenetics, in melanoma cells.

scholarly journals Structure and Function of ATP-Dependent Chromatin Remodeling Complexes in Human Cancer

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-48-SCI-48
Author(s):  
Cigall Kadoch
Keyword(s):  
Chromatin Remodeling ◽  
Developmental Disorders ◽  
Human Cancer ◽  
Malignant Rhabdoid Tumor ◽  
Advisory Committees ◽  
Sequencing Studies ◽  
Genes Encoding ◽  
Therapeutic Development ◽  
Chromatin Remodeling Complexes ◽  
And Function

Dr. Cigall Kadoch will discuss how recent exome-and genome-wide sequencing studies in human cancers have unmasked a striking frequency of mutations in the genes encoding subunits of the mammalian SWI/SNF (mSWI/SNF) family of ATP-dependent chromatin remodeling complexes. Her laboratory uses biochemistry, structural biology, systems biology, and genomics-based approaches to define the mechanisms of chromatin and gene regulation carried out by the mSWI/SNF family of chromatin regulators. Specifically, they have studied rare, genetically well-defined pediatric cancers including synovial sarcoma, Ewing sarcoma, malignant rhabdoid tumor and others, all of which involve mSWI/SNF complex perturbations as critical drivers of their oncogenic programs. These studies have informed the diverse mechanisms underlying mSWI/SNF complex targeting and function in a wide array of cancers (including hematologic cancers) and developmental disorders and have provided new foundations for therapeutic development. Disclosures Kadoch: Foghorn Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Adherent invasive Escherichia coli (AIEC) strain LF82, but not Candida albicans, plays a profibrogenic role in the intestine

Gut Pathogens ◽  
2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Dina Chokr ◽  
Marjorie Cornu ◽  
Christel Neut ◽  
Clovis Bortolus ◽  
Rogatien Charlet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Escherichia Coli ◽  
Candida Albicans ◽  
Proinflammatory Cytokines ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Cell ◽  
Inflammatory Cells ◽  
Mesenchymal Transition ◽  
Intestinal Fibrosis ◽  
Tgf Β1

Abstract Background Intestinal fibrosis is a frequent complication of Crohn’s disease. However, the factors that cause chronicity and promote fibrogenesis are not yet understood. Aims In the present study, we evaluated the profibrotic effects of adherent-invasive Escherichia coli (AIEC) LF82 strain and Candida albicans in the gut. Methods Colonic fibrosis was induced in C57BL/6 mice by administration of three cycles of 2.5% (w/v) dextran sulfate sodium (DSS) for 5 weeks. LF82 and C. albicans were administered orally once at the start of each week or each cycle, respectively. Expression of markers of myofibroblast activation was determined in TGF-β1-stimulated human intestinal epithelial cells (IECs). Results LF82 administration exacerbated fibrosis in DSS-treated mice, revealed by increased colonic collagen deposition and expression of the profibrotic genes Col1a1, Col3a1, Fn1 and Vim. This was accompanied by enhanced gene expression of proinflammatory cytokines and chemokines, as well as more recruited inflammatory cells into the intestine. LF82 also potentiated TGF-β1-stimulated epithelial–mesenchymal transition and myofibroblast activation in IECs, by further inducing gene expression of the main mesenchymal cell markers FN1 and VIM and downregulating the IEC marker OCLN. Proinflammatory cytokines were overexpressed with LF82 in TGF-β1-stimulated IECs. Conversely, C. albicans did not affect intestinal fibrosis progression in DSS-treated mice or myofibroblast activation in TGF-β1-stimulated IECs. Conclusions These results demonstrate that AIEC strain LF82, but not C. albicans, may play a major profibrogenic role in the gut.

scholarly journals A Novel Mechanism of Antagonism between ATP-Dependent Chromatin Remodeling Complexes Regulates RNR3 Expression

2009 ◽  
Vol 29 (12) ◽  
pp. 3255-3265 ◽  
Author(s):  
Raghuvir S. Tomar ◽  
James N. Psathas ◽  
Hesheng Zhang ◽  
Zhengjian Zhang ◽  
Joseph C. Reese
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Chromatin Structure ◽  
Large Subunit ◽  
Nucleosome Positioning ◽  
Gene Encoding ◽  
Control Of Gene Expression ◽  
Dna Binding Factors ◽  
Chromatin Remodeling Complexes

ABSTRACT Gene expression depends upon the antagonistic actions of chromatin remodeling complexes. While this has been studied extensively for the enzymes that covalently modify the tails of histones, the mechanism of how ATP-dependent remodeling complexes antagonize each other to maintain the proper level of gene activity is not known. The gene encoding a large subunit of ribonucleotide reductase, RNR3, is regulated by ISW2 and SWI/SNF, complexes that repress and activate transcription, respectively. Here, we studied the functional interactions of these two complexes at RNR3. Deletion of ISW2 causes constitutive recruitment of SWI/SNF, and conditional reexpression of ISW2 causes the repositioning of nucleosomes and reduced SWI/SNF occupancy at RNR3. Thus, ISW2 is required for restriction of access of SWI/SNF to the RNR3 promoter under the uninduced condition. Interestingly, the binding of sequence-specific DNA binding factors and the general transcription machinery are unaffected by the status of ISW2, suggesting that disruption of nucleosome positioning does not cause a nonspecific increase in cross-linking of all factors to RNR3. We provide evidence that ISW2 does not act on SWI/SNF directly but excludes its occupancy by positioning nucleosomes over the promoter. Genetic disruption of nucleosome positioning by other means led to a similar phenotype, linking repressed chromatin structure to SWI/SNF exclusion. Thus, incorporation of promoters into a repressive chromatin structure is essential for prevention of the opportunistic actions of nucleosome-disrupting activities in vivo, providing a novel mechanism for maintaining tight control of gene expression.

scholarly journals Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression

2020 ◽  
Vol 117 (44) ◽  
pp. 27354-27364 ◽  
Author(s):  
Siddhant U. Jain ◽  
Sima Khazaei ◽  
Dylan M. Marchione ◽  
Stefan M. Lundgren ◽  
Xiaoshi Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Tumor Development ◽  
Gene Expression Profiles ◽  
Osteoblastic Differentiation ◽  
Missense Mutations ◽  
Giant Cell Tumors ◽  
H3k36 Methylation ◽  
Genes Encoding

A high percentage of pediatric gliomas and bone tumors reportedly harbor missense mutations at glycine 34 in genes encoding histone variant H3.3. We find that these H3.3 G34 mutations directly alter the enhancer chromatin landscape of mesenchymal stem cells by impeding methylation at lysine 36 on histone H3 (H3K36) by SETD2, but not by the NSD1/2 enzymes. The reduction of H3K36 methylation by G34 mutations promotes an aberrant gain of PRC2-mediated H3K27me2/3 and loss of H3K27ac at active enhancers containing SETD2 activity. This altered histone modification profile promotes a unique gene expression profile that supports enhanced tumor development in vivo. Our findings are mirrored in G34W-containing giant cell tumors of bone where patient-derived stromal cells exhibit gene expression profiles associated with early osteoblastic differentiation. Overall, we demonstrate that H3.3 G34 oncohistones selectively promote PRC2 activity by interfering with SETD2-mediated H3K36 methylation. We propose that PRC2-mediated silencing of enhancers involved in cell differentiation represents a potential mechanism by which H3.3 G34 mutations drive these tumors.

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