The Drosophila Brahma (SWI/SNF) chromatin remodeling complex exhibits cell-type specific activation and repression functions

Marenda, Daniel R.; Zraly, Claudia B.; Dingwall, Andrew K.

doi:10.1016/j.ydbio.2003.10.040

Cited by 55 publications

(63 citation statements)

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“…Subsequently, whole-genome expression analysis in yeast demonstrated a role for the Swi͞Snf complex in transcriptional repression as well as activation. Intriguingly, studies examining wing vein development in Drosophila suggest that SNR1, the Snf5 Drosophila ortholog, may repress transcriptional activation by the ATPase Brm, a core Swi͞Snf subunit (22). We found that three times as many genes were activated (978) as repressed (322) after Snf5 inactivation in MEFs, suggesting that mammalian Snf5 may in fact act to repress transcriptional activation by the Swi͞Snf complex.…”

Section: Discussionmentioning

confidence: 59%

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation

Isakoff

Sansam

Tamayo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

199

208

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Snf5 (Ini1͞Baf47͞Smarcb1), a core member of the Swi͞Snf chromatin remodeling complex, is a potent tumor suppressor whose mechanism of action is largely unknown. Biallelic loss of Snf5 leads to the onset of aggressive cancers in both humans and mice. We have developed an innovative and widely applicable analytical technique for cross-species validation of cancer models and show that the gene expression profiles of our Snf5 murine models closely resemble those of human Snf5-deficient rhabdoid tumors. We exploit this system to produce what we believe to be the first report documenting the effects on gene expression of inactivating a Swi͞Snf subunit in normal mammalian cells and to identify the transcriptional pathways regulated by Snf5. We demonstrate that the tumor suppressor activity of Snf5 depends on its regulation of cell cycle progression; Snf5 inactivation leads to aberrant upregulation of E2F targets and increased levels of p53 that are accompanied by apoptosis, polyploidy, and growth arrest. Further, conditional mouse models demonstrate that inactivation of p16Ink4a or Rb (retinoblastoma) does not accelerate tumor formation in Snf5 conditional mice, whereas mutation of p53 leads to a dramatic acceleration of tumor formation.chromatin remodeling ͉ gene expression analysis ͉ mouse models ͉ Swi͞Snf

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Section: Discussionmentioning

confidence: 59%

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation

Isakoff

Sansam

Tamayo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

199

208

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“…Genetic Manipulations and Strains-Fly strains and manipulations used in this study have been previously described (15,16,39 (47), was controlled using the P(GawB)69B-GAL4 driver (48). Crosses were carried out at 18°C and appropriately staged pupae selected for RNA analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we found that SNR1 functions to mediate aspects of Brm complex transcriptional repression in specific cells through shielding ATP-dependent gene activation, a mechanism that requires the coordinated activities of a tissue-specific transcription repressor and histone deacetylase activity (39). Taking advantage of conditional dominant-negative mutant alleles of snr1 and brm, we showed that cell-type or tissuespecific regulation of Brm complex activities may play an essential role in regulating key developmental growth and patterning processes (16,23,39).…”

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confidence: 99%

“…Taking advantage of conditional dominant-negative mutant alleles of snr1 and brm, we showed that cell-type or tissuespecific regulation of Brm complex activities may play an essential role in regulating key developmental growth and patterning processes (16,23,39). This regulation involves epigenetic coregulators, such as transcription factors or enzymes that lead to modification of histones, including histone acetyltransferases or deacetylases to prevent inappropriate expression of critical target genes (23,39,40). The dominant-negative mutant alleles produce proteins that are stable and incorporated into Brm complexes, where the mutant phenotypes arise from loss of subunit function and reflect important contributions of the affected subunit to whole complex activities on in vivo target genes.…”

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confidence: 99%

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Hormone-response Genes Are Direct in Vivo Regulatory Targets of Brahma (SWI/SNF) Complex Function

Zraly

Middleton

Dingwall

2006

Journal of Biological Chemistry

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Metazoan SWI/SNF chromatin remodeling complexes exhibit ATP-dependent activation and repression of target genes. The Drosophila Brahma (SWI/SNF) complex subunits BRM and SNR1 are highly conserved with direct counterparts in yeast (SWI2/SNF2 and SNF5) and mammals (BRG1/hBRM and INI1/hSNF5). BRM encodes the catalytic ATPase required for chromatin remodeling and SNR1 is a regulatory subunit. Importantly, SNR1 mediates ATP-independent repression functions of the complex in cooperation with histone deacetylases and direct contacts with gene-specific repressors. SNR1 and INI1, as components of their respective SWI/SNF complexes, are important for developmental growth control and patterning, with direct function as a tumor suppressor. To identify direct regulatory targets of the Brm complex, we performed oligonucleotidebased transcriptome microarray analyses using RNA isolated from mutant fly strains harboring dominant-negative alleles of snr1 and brm. Steady-state RNA isolated from early pupae was examined, as this developmental stage critically requires Brm complex function. We found the hormone-responsive Ecdysone-induced genes (Eig) were strongly misregulated and that the Brm complex is directly associated with the promoter regions of these genes in vivo. Our results reveal that the Brm complex assists in coordinating hormone-dependent transcription regulation of the Eig genes.The metazoan SWI/SNF ATP-dependent chromatin remodeling complexes are large (1.2 MDa, 8 -11 subunits) multimeric assemblies that act to modify nucleosome structure, allowing for activation or repression of gene transcription (1, 2). Prevailing models suggest that the SWI/SNF complexes are recruited to specific in vivo targets through interactions with DNA-binding transcription factors, where the ATP-dependent activities of the complex assist in gene regulation through changes in DNA-histone contacts (3, 4). Subsequently, the affected nucleosomes can be covalently modified to maintain active or repressed transcription through cooperation with histone acetyltransferases and histone deacetylase complexes (5).Whole genome analyses of yeast and mammalian SWI/SNF complex mutants revealed that the expression of ϳ5% of all genes was affected by removal of the complex (6, 7). Importantly, whereas there was a detectable reduction in the expression of a small subset of genes, more transcripts were induced upon loss of the gene encoding the core ATPase (SNF2/SWI2), suggesting that the complex had direct roles in both gene activation and repression. In fact, both epigenetic functions of the yeast complex appear to rely on the ATPase activity of SNF2/ SWI2 (8). Although the yeast SWI/SNF complex is not required for vegetative growth, the metazoan SWI/SNF complex counterparts, including the Brahma (Brm) complex in Drosophila (9, 10) and the related mammalian hBrm/Brg1 complexes (11), are essential (12, 13). This requirement may be due to direct involvement of the Brm complexes in facilitating global gene expression by RNA polymerase II (14).The snr1 gene (S...

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“…Although both major classes of chromatin remodeling complexes are likely to contribute to developmental processes, including those in the central nervous system (19 -21), evidence is emerging that the SWI/SNF chromatin remodeling complexes play an important role in the differentiation of specific cell types (22). For example, these complexes have been shown to facilitate the differentiation of a variety of cell types such as erythrocytes (7,23), macrophages (24), myeloid cells (25), adipocytes (26), myoblasts (27), osteoblasts (28), neurons (29,30), and glia (31).…”

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confidence: 99%

SWI/SNF Chromatin Remodeling ATPase Brm Regulates the Differentiation of Early Retinal Stem Cells/Progenitors by Influencing Brn3b Expression and Notch Signaling

Das

James

Bhattacharya

et al. 2007

Journal of Biological Chemistry

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Based on a variety of approaches, evidence suggests that different cell types in the vertebrate retina are generated by multipotential progenitors in response to interactions between cell intrinsic and cell extrinsic factors. The identity of some of the cellular determinants that mediate such interactions has emerged, shedding light on mechanisms underlying cell differentiation. For example, we know now that Notch signaling mediates the influence of the microenvironment on states of commitment of the progenitors by activating transcriptional repressors. Cell intrinsic factors such as the proneural basic helix-loop-helix and homeodomain transcription factors regulate a network of genes necessary for cell differentiation and maturation. What is missing from this picture is the role of developmental chromatin remodeling in coordinating the expression of disparate classes of genes for the differentiation of retinal progenitors. Here we describe the role of Brm, an ATPase in the SWI/SNF chromatin remodeling complex, in the differentiation of retinal progenitors into retinal ganglion cells. Using the perturbation of expression and function analyses, we demonstrate that Brm promotes retinal ganglion cell differentiation by facilitating the expression and function of a key regulator of retinal ganglion cells, Brn3b, and the inhibition of Notch signaling. In addition, we demonstrate that Brm promotes cell cycle exit during retinal ganglion cell differentiation. Together, our results suggest that Brm represents one of the nexus where diverse information of cell differentiation is integrated during cell differentiation.Cell fate specification and subsequent cell differentiation in the nervous system are orchestrated and finessed by interplay between cell intrinsic and cell extrinsic factors. This process is exemplified during the development of the retina, an excellent model of the central nervous system. Recent evidence suggests that disparate transcription factors belonging to basic helixloop-helix, homeodomain, and zinc finger classes cooperate toward lineage specification and differentiation (1-6). For example, the basic helix-loop-helix transcription factor, Math5, and the homeodomain transcription factor, Pax6, have been shown to cooperate during the specification of retinal progenitors into retinal ganglion cells (RGCs) 2 (2, 7-9). As progenitors are committed along RGC lineage, Wt1, a zinc finger transcription factor, and Brn3b, a homeodomain transcription factor of POU class, are expressed and ultimately promote the differentiation and maturation of the specified progenitors into RGCs (10). The progress in the identification of intrinsic factors has been paralleled by the characterization of extrinsic factors and intercellular signaling pathways, e.g. Notch pathway, that mediates the regulatory influence of the microenvironment on retinal progenitors' maintenance and their differentiation into .Although the identification of cell intrinsic and cell extrinsic factors has helped our understanding of the mechanisms t...

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The Drosophila Brahma (SWI/SNF) chromatin remodeling complex exhibits cell-type specific activation and repression functions

Cited by 55 publications

References 78 publications

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation

Hormone-response Genes Are Direct in Vivo Regulatory Targets of Brahma (SWI/SNF) Complex Function

SWI/SNF Chromatin Remodeling ATPase Brm Regulates the Differentiation of Early Retinal Stem Cells/Progenitors by Influencing Brn3b Expression and Notch Signaling

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