Activation of the mouse cytokeratin A (<i>endo A</i>) gene in teratocarcinoma F9 cells by the histone deacetylase inhibitor Trichostatin A

Miyashita, Tomoyuki; Yamamoto, Hideyuki; Nishimune, Yoshitake; Nozaki, Masami; Morita, Takashi; Matsushiro, Aizo

doi:10.1016/0014-5793(94)01034-x

Cited by 25 publications

(15 citation statements)

References 29 publications

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“…Nevertheless, indirect evidence, such as the growth inhibition of the cells by TSA treatment and increased MIC2 expression over the TSA treatment time course (Fig. 4A), are consistent with other studies that show that TSA inhibits cell proliferation (34) and increases the expression of active genes (31,32), indicating that TSA is functioning in these cells.…”

Section: De Novo Methylation Of the Human Hprt 5јsupporting

confidence: 91%

“…4A. While TSA treatment did appear to enhance the expression level of the control MIC2 gene (an X-linked gene which escapes inactivation), as has been previously observed in other gene systems (31,32), it failed to re-activate the HPRT gene on the inactive X chromosome in both cell lines as determined by RT-PCR (Fig. 4A).…”

Section: De Novo Methylation Of the Human Hprt 5јsupporting

confidence: 74%

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Evidence That Silencing of the HPRT Promoter by DNA Methylation Is Mediated by Critical CpG Sites

Chen¹,

Yang²,

Yang³

2001

Journal of Biological Chemistry

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The strong correlation between promoter hypermethylation and gene silencing suggests that promoter methylation represses transcription. To identify methylation sites that may be critical for maintaining repression of the human HPRT gene, we treated human/hamster hybrid cells containing an inactive human X chromosome with the DNA demethylating agent 5-azadeoxycytidine (5aCdr), and we then examined the high resolution methylation pattern of the HPRT promoter in single cell-derived lines. Reactivation of HPRT correlated with complete promoter demethylation. In contrast, the 61 5aCdr-treated clones that failed to reactivate HPRT exhibited sporadic promoter demethylation. However, three specific CpG sites remained methylated in all unreactivated clones, suggesting these sites may be critical for maintaining transcriptional silencing of the HPRT gene. Re-treatment of partially demethylated (and unreactivated) clones with a second round of 5aCdr did not increase the frequency of HPRT reactivation. This is consistent with mechanisms of methylation-mediated repression requiring methylation at specific critical sites and argues against models invoking overall levels or a threshold of promoter methylation. Treatment of cells with the histone deacetylase inhibitor, trichostatin A, failed to reactivate HPRT on the inactive X chromosome, even when the promoter was partially demethylated by 5aCdr treatment, suggesting that transcriptional repression by DNA methylation is unlikely to depend upon a trichostatin A-sensitive histone deacetylase.In mammals, DNA methylation at CpG dinucleotides in the 5Ј region of genes is frequently associated with transcriptional silencing (1), particularly in housekeeping genes on the inactive X chromosome. Numerous studies suggest that this association between promoter hypermethylation and transcriptional repression has a functional basis. For instance, individual loci on the inactive human X chromosome in human/ hamster hybrid cell lines may be reactivated using DNA-demethylating agents such as 5-azacytidine (2, 3) and 5-azadeoxycytidine, which inhibit the maintenance methyltransferase and incorporate into newly synthesized DNA (4), resulting in a failure to maintain methylation patterns during growth. Likewise, in vitro methylation of various promoter constructs results in inhibition of transcription in transient expression assays (5-9). However, despite significant evidence that DNA methylation represses transcription, specific mechanisms of this repression are only now becoming apparent.Recent reports suggest that DNA methylation mediates transcriptional repression indirectly, via binding of the methylated DNA-binding protein MeCP2, which in turn recruits histone deacetylases that modify the local chromatin structure (10, 11). However, additional mechanisms may also act to repress transcription by methylation, such as direct inhibition of transcription factor binding to its cognate site in DNA. Indeed, methylation of the binding sites of several transcription factors has been shown to alter ...

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Section: De Novo Methylation Of the Human Hprt 5јsupporting

confidence: 91%

Section: De Novo Methylation Of the Human Hprt 5јsupporting

confidence: 74%

Evidence That Silencing of the HPRT Promoter by DNA Methylation Is Mediated by Critical CpG Sites

Chen¹,

Yang²,

Yang³

2001

Journal of Biological Chemistry

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“…Inhibition of HDAC activity activates transcription and causes a change in endonuclease sensitivity at several promoters (7,16,39,56). Despite the fact that the DNase I-hypersensitive site was present in the Rb-defective cells, we wished to determine whether HDAC inhibitors could restore HLA-DRA and -DRB mRNA expression in these cells.…”

Section: Resultsmentioning

confidence: 99%

Histone Deacetylase Activity Represses Gamma Interferon-Inducible HLA-DR Gene Expression following the Establishment of a DNase I-Hypersensitive Chromatin Conformation

Osborne¹,

Zhang²,

Yang

et al. 2001

Molecular and Cellular Biology

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Expression of the retinoblastoma tumor suppressor protein (Rb) is required for gamma interferon (IFN-␥Major histocompatibility complex (MHC) class II molecules are heterodimeric cell surface glycoproteins comprised of both a heavy (alpha) chain and a light (beta) chain. MHC class II molecules (HLA-DR, -DP, and -DQ in humans) bind and display peptide antigens for recognition by CD4 ϩ T lymphocytes. Recognition of the MHC class II heterodimer-antigen complex by the T-cell receptor and the accessory protein CD4 of T lymphocytes leads to the generation of an immune response. MHC class II molecules play an important role in antitumor immunity (1-4, 11, 29, 42-44, 49). Specifically, transfection of tumor cells with syngeneic murine MHC class II genes immunizes mice against MHC class II-negative parental tumor cells (2). Vaccination of mice using this protocol also leads to eradication of an MHC class II-negative, basement membrane-invasive tumor (4). Also, tumor-specific antigens capable of eliciting HLA class II-restricted activation of tumorinfiltrating T lymphocytes have been identified (46,57,58).MHC class II expression is constitutively activated during development in professional antigen-presenting cells, such as B cells, dendritic cells, and macrophages; it is inducible by cytokines, most importantly, gamma interferon (IFN-␥), in nearly all other types of cells. MHC class II expression is regulated primarily at the level of transcription through promoter elements that are conserved among the MHC class II genes and the genes encoding accessory molecules such as the invariant chain, the MHC class II chaperone. The elements are, from 5Ј to 3Ј, S box, X1 box, X2 box, Y box, and TATA box. The transactivators RFX, X2BP (CREB), and NF-Y are required factors for MHC class II gene activation and bind the X1, X2, and Y boxes, respectively. Cooperative interactions between transactivators bound to the X and Y elements have been demonstrated to be essential for the establishment of promoter occupancy and the transcription of class II genes (60). In particular, binding of the Y box factor, NF-Y, has been demonstrated to be required for occupancy of the other promoter elements and for IFN-␥-inducible MHC class II gene expression (60). In addition to the promoter binding factors, the class II transactivator (CIITA) is a required coactivator that functions by interaction with and stabilization of the transcription factors previously assembled on MHC class II promoters (20,24,38,53,59,68).It has been shown that the retinoblastoma tumor suppressor protein (Rb) is also required for IFN-␥-inducible MHC class II gene expression (34,35,41,67). Several Rb-defective human tumor cell lines exhibit a loss of IFN-␥-inducible MHC class II gene expression that is rescued by the reexpression of func-* Corresponding author. Mailing address:

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“…Another important step toward the understanding of the role of histone acetylation was the identification of specific inhibitors of histone deacetylases (12; for a review, see reference 77). Trichostatin A, a fungistatic antibiotic, has been shown to induce differentiation in erythroleukemia cells (78), to block the development of Xenopus and starfish embryos (2), to induce the expression of different genes (5,20,25,43), and to arrest normal fibroblasts in the G 1 or G 2 phase of the cell cycle (76). Furthermore, trichostatin A and trapoxin, another specific inhibitor of histone deacetylases, also have the potential to revert the phenotype of oncogene-transformed fibroblasts (17,62,75).…”

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confidence: 99%

Identification of Mouse Histone Deacetylase 1 as a Growth Factor-Inducible Gene

Bartl

Taplick

Lagger

et al. 1997

Molecular and Cellular Biology

115

100

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Reversible acetylation of core histones plays an important role in transcriptional regulation, cell cycle progression, and developmental events. The acetylation state of histones is controlled by the activities of acetylating and deacetylating enzymes. By using differential mRNA display, we have identified a mouse histone deacetylase gene, HD1, as an interleukin-2-inducible gene in murine T cells. Sequence alignments revealed that murine HD1 is highly homologous to the yeast RPD3 pleiotropic transcriptional regulator. Indirect immunofluorescence microscopy proved that mouse HD1 is a nuclear protein. When expressed in yeast, murine HD1 was also detected in the nucleus, although it failed to complement the rpd3⌬ deletion phenotype. HD1 mRNA expression was low in G 0 mouse cells but increased when the cells crossed the G 1 /S boundary after growth stimulation. Immunoprecipitation experiments and functional in vitro assays showed that HD1 protein is associated with histone deacetylase activity. Both HD1 protein levels and total histone deacetylase activity increased upon interleukin-2 stimulation of resting B6.1 cells. When coexpressed with a luciferase reporter construct, HD1 acted as a negative regulator of the Rous sarcoma virus enhancer/promoter. HD1 overexpression in stably transfected Swiss 3T3 cells caused a severe delay during the G 2 /M phases of the cell cycle. Our results indicate that balanced histone acetylation/deacetylation is crucial for normal cell cycle progression of mammalian cells.

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Activation of the mouse cytokeratin A (endo A) gene in teratocarcinoma F9 cells by the histone deacetylase inhibitor Trichostatin A

Cited by 25 publications

References 29 publications

Evidence That Silencing of the HPRT Promoter by DNA Methylation Is Mediated by Critical CpG Sites

Evidence That Silencing of the HPRT Promoter by DNA Methylation Is Mediated by Critical CpG Sites

Histone Deacetylase Activity Represses Gamma Interferon-Inducible HLA-DR Gene Expression following the Establishment of a DNase I-Hypersensitive Chromatin Conformation

Identification of Mouse Histone Deacetylase 1 as a Growth Factor-Inducible Gene

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