An RNAi Screen of Chromatin Proteins Identifies Tip60-p400 as a Regulator of Embryonic Stem Cell Identity

Fazzio, Thomas G.; Huff, Jason T.; Panning, Barbara

doi:10.1016/j.cell.2008.05.031

Cited by 416 publications

(534 citation statements)

References 48 publications

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“…Thus, p400/mDomino appears to regulate both the p53-dependent and c-Myc-modulated expression of p21, which blocks cell proliferation and leads to cellular senescence. However, a recent study showed that the siRNA-mediated knockdown of p400/mDomino in mouse cells reduces the proliferation rate of embryonic stem cells without p21 up-regulation, and has only a modest effect on the cell cycle of embryonic fibroblasts (23). This discrepancy in the effect of p400 knockdown on cellular proliferation could be attributable to cell-type-specific roles of p400/mDomino, or different levels of residual p400/mDomino protein might have resulted in the distinct phenotypes in these knockdown experiments.…”

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confidence: 99%

Essential Role of p400/mDomino Chromatin-remodeling ATPase in Bone Marrow Hematopoiesis and Cell-cycle Progression

Fujii

Ueda

Nagata

et al. 2010

Journal of Biological Chemistry

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p400/mDomino is an ATP-dependent chromatin-remodeling protein that catalyzes the deposition of histone variant H2A.Z into nucleosomes to regulate gene expression. We previously showed that p400/mDomino is essential for embryonic development and primitive hematopoiesis. Here we generated a conditional knock-out mouse for the p400/mDomino gene and investigated the role of p400/mDomino in adult bone marrow hematopoiesis and in the cell-cycle progression of embryonic fibroblasts. The Mx1-Cre-mediated deletion of p400/mDomino resulted in an acute loss of nucleated cells in the bone marrow, including committed myeloid and erythroid cells as well as hematopoietic progenitor and stem cells. A hematopoietic colony assay revealed a drastic reduction in colony-forming activity after the deletion of p400/mDomino. Moreover, the loss of p400/mDomino in mouse embryonic fibroblasts (MEFs) resulted in strong growth inhibition. Cell-cycle analysis revealed that the mDomino-deficient MEFs exhibited a pleiotropic cellcycle defect at the S and G 2 /M phases, and polyploid and multinucleated cells with micronuclei emerged. DNA microarray analysis revealed that the p400/mDomino deletion from MEFs caused the impaired expression of many cell-cycle-regulatory genes, including G 2 /M-specific genes targeted by the transcription factors FoxM1 and c-Myc. These results indicate that p400/ mDomino plays a key role in cellular proliferation by controlling the expression of cell-cycle-regulatory genes.The alteration of chromatin structure and function is a critical process in the transcriptional activation or repression of various cell-type-specific or developmentally regulated genes and is mainly executed by covalent histone modification and ATP-hydrolysis-dependent chromatin remodeling. All of the ATP-dependent chromatin remodelers are multisubunit protein complexes containing a SWI2/SNF2 family ATPase subunit, which plays a central role in chromatin-remodeling activities (1, 2). p400/mammalian Domino (p400/mDomino, 3 Gene symbol: Ep400), which was identified as an interaction partner for adenovirus E1A (3) and a myeloid-specific transcription factor, MZF-2A (4), is an SWR1-class chromatin-remodeling ATPase that is homologous to the yeast Swr1p and Drosophila Domino proteins (5, 6). The p400/ mDomino-containing protein complex consists of more than 10 subunits, including the Tip60 histone acetyltransferase and a PI3K family protein kinase TRRAP (3,7,8). The SWR1-class remodelers are responsible for the regulated exchange of selective histone H2A variants, such as H2A.Z, with the canonical H2A in nucleosomes (5, 9 -11). This histone-exchanging activity plays a key role in the epigenetic regulation of gene expression as well as in DNA repair (12-16). p400/mDomino is known to interact physically and/or functionally with growth-regulating transcription factors, such as Myc, p53, E2F, and adenovirus E1A (3,(17)(18)(19)(20). In primary human fibroblasts and osteosarcoma-derived U2OS cells, the knockdown of p400/mDomino results in cell-cycle arrest ...

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confidence: 99%

Essential Role of p400/mDomino Chromatin-remodeling ATPase in Bone Marrow Hematopoiesis and Cell-cycle Progression

Fujii

Ueda

Nagata

et al. 2010

Journal of Biological Chemistry

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“…Tip60 depletion in Caenorhabditis elegans results in premature cell cycle exit and differentiation of one particular cell type, the vulval cells 45 . Second, Tip60 was shown to be essential for the maintenance of embryonic stem cell identity, probably through regulation of the cell cycle and proliferation and by repressing the expression of multiple differentiation genes 39 . Interestingly, Tip60 knockdown had only very modest effects on MEF cell cycle distribution and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60

et al. 2013

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Transcriptional coregulators, including the acetyltransferase Tip60, have a key role in complex cellular processes such as differentiation. Whereas post-translational modifications have emerged as an important mechanism to regulate transcriptional coregulator activity, the identification of the corresponding demodifying enzymes has remained elusive. Here we show that the expression of the Tip60 protein, which is essential for adipocyte differentiation, is regulated through polyubiquitination on multiple residues. USP7, a dominant deubiquitinating enzyme in 3T3-L1 adipocytes and mouse adipose tissue, deubiquitinates Tip60 both in intact cells and in vitro and increases Tip60 protein levels. Furthermore, inhibition of USP7 expression and activity decreases adipogenesis. Transcriptome analysis reveals several cell cycle genes to be co-regulated by both Tip60 and USP7. Knockdown of either factor results in impaired mitotic clonal expansion, an early step in adipogenesis. These results reveal deubiquitination of a transcriptional coregulator to be a key mechanism in the regulation of early adipogenesis.

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“…Several genome-wide RNAi screens have identified factors required for self-renewal, and cohesin and condensin have shown up time and time again [13,[63][64][65][66]. Since self-renewal implies proliferation, these screens will identify a large fraction of genes required for DNA replication, repair and cell division.…”

Section: A Role For Cohesin In Gene Expression and Development: Disenmentioning

confidence: 99%

Cohesin and chromatin organisation

Seitan

Merkenschlager

2012

Current Opinion in Genetics & Development

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An RNAi Screen of Chromatin Proteins Identifies Tip60-p400 as a Regulator of Embryonic Stem Cell Identity

Cited by 416 publications

References 48 publications

Essential Role of p400/mDomino Chromatin-remodeling ATPase in Bone Marrow Hematopoiesis and Cell-cycle Progression

Essential Role of p400/mDomino Chromatin-remodeling ATPase in Bone Marrow Hematopoiesis and Cell-cycle Progression

Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60

Cohesin and chromatin organisation

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