The SWI/SNF chromatin-remodeling complex subunit SNF5 is essential for hepatocyte differentiation

Gresh, Lionel; Bourachot, Brigitte; Reimann, Andreas; Guigas, Bruno; Fiette, Laurence; Garbay, Serge; Muchardt, Christian; Hue, Louis; Pontoglio, Marco; Yaniv, Moshe; Klochendler-Yeivin, Agnès

doi:10.1038/sj.emboj.7600802

Cited by 84 publications

(76 citation statements)

References 66 publications

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“…A recent report using rhabdoid tumor-derived cell lines that lack INI1/hSNF5 suggested that it may not be required for all BRG1-dependent transcription activation functions (64). Inactivation of INI1/hSNF5 in the developing murine liver using Cre-mediated recombination results in increased proliferation and defects in glycogen storage (7). Following INI1/hSNF5 inactivation, transcriptome analysis revealed defective activation of ϳ70% of the genes normally up-regulated during liver development, including genes involved in glycogen metabolism and cell-cell adhesion.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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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“…The tumor suppressor role of the SNF5/ INI1 subunit may not be limited to cell-cycle regulation but may also rely on cytoskeleton organization and DNA damage signaling (Medjkane et al, 2004;Klochendler-Yeivin et al, 2006). Finally, a role for SNF5/ INI1 in differentiation is suggested by recent data showing that the liver-specific inactivation of Snf5/Ini1 in mice compromises hepatocyte differentiation (Gresh et al, 2005).…”

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confidence: 99%

The requirement for SNF5/INI1 in adipocyte differentiation highlights new features of malignant rhabdoid tumors

et al. 2007

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ATP-dependent SWI/SNF chromatin remodeling complexes regulate cell-cycle and play critical roles in a variety of differentiation pathways. The core subunit SNF5/INI1 is a tumor suppressor that is inactivated in a highly aggressive childhood cancer of unknown cellular origin, termed malignant rhabdoid tumor (MRT). The highly undifferentiated phenotype of this tumor suggests that the loss-of-function of hSNF5/INI1 impairs specific differentiation programs of the MRT parental cell. Based on the hypothesis that these programs might be reinitialized upon hSNF5/INI1 re-expression in MRTs, we show that some MRT cell lines can differentiate toward the adipogenic lineage. We further show that the knock down of the SNF5/INI1 subunit abrogates adipocyte differentiation of murine 3T3-L1 preadipocytes and of human mesenchymal stem cells. Finally, we provide evidence that hSNF5/INI1 cooperates with C/EBPb and PPARc2 transcriptional regulators to activate the expression of adipocyte-specific genes. These data indicate that not only the ATPase subunit of the SWI/SNF complex, but also SNF5/INI1 is required for adipocyte differentiation. They further show that MRT cell lines harbor an adipogenic differentiation potential and that the tumor suppressor role of the SNF5/INI1 subunit may rely on its ability to regulate the balance between cell proliferation and differentiation.

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“…Directly or through its function in the SWI/ SNF complex, INi1 represses or activates a large number of genes required for early stage development. Gresh, et al, 11 recently inactivated Ini1 in the developing liver, which led to early postnatal lethality. Mice that are Ini1/Snf5 haploinsufficient develop tumors that resemble RTs histologically, but these tumors arise most often in soft tissues, often on the face.…”

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Molecular genetics of atypical teratoid/rhabdoid tumors

Biegel¹

2006

FOC

223

153

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Rhabdoid tumors are extremely aggressive malignancies that generally occur in infants and young children. The most common locations are the kidney and central nervous system (atypical teratoid/rhabdoid tumor [RT]), although RTs can also arise in most soft-tissue sites. Rhabdoid tumors in all anatomical locations have a similar molecular origin. Mutation or deletion of both copies of the hSNF5/INI1 gene that maps to chromosome band 22q11.2 is observed in approximately 70% of primary tumors. An additional 20 to 25% of tumors have reduced expression at the RNA or protein level, indicative of a loss-of-function event. The INI1 protein is a component of the SWI/SNF chromatin-remodeling complex. The complex is recruited to promoters of a large variety of genes involved in cell signaling, growth, and differentiation. This review summarizes what is currently known regarding the molecular genetics of RTs.

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The SWI/SNF chromatin-remodeling complex subunit SNF5 is essential for hepatocyte differentiation

Cited by 84 publications

References 66 publications

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

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

The requirement for SNF5/INI1 in adipocyte differentiation highlights new features of malignant rhabdoid tumors

Molecular genetics of atypical teratoid/rhabdoid tumors

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