Chromatin remodeling and transcriptional activation: the cast (in order of appearance)

Urnov, Fyodor D.; Wolffe, Alan P.

doi:10.1038/sj.onc.1204323

Cited by 176 publications

(153 citation statements)

References 151 publications

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“…Modifications of histone proteins are -together with DNA methylation -the most important group of epigenetic alterations [6]. Of these, the balance between histone acetylation and deacetylation is arguably the most investigated.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

et al. 2016

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Reduced activity of histone deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here, we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics. Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD, miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved in anti-miR-223-treated cells. Direct miRNAtarget interaction was confirmed by reporter gene assay. In a next step, reduced expression of HDAC2 was found to increase the levels of the chemokine fractalkine (CX3CL1). In vivo studies confirmed elevated expression levels of miR-223 in mice exposed to cigarette smoke and in emphysematous lung tissue from LPS-treated mice. Moreover, a significant inverse correlation of miR-223 and HDAC2 expression was found in two independent cohorts of COPD patients. These data emphasize that miR-223, the most prevalent miRNA in COPD, controls expression and activity of HDAC2 in pulmonary cells, which, in turn, might alter the expression profile of chemokines. This pathway provides a novel pathogenic link between dysregulated miRNA expression and epigenetic activity in COPD. KEY MESSAGES: Histone deacetylase 2 is directly targeted by miR-223. Levels of miR-223 are induced by interleukin-1 and tumor necrosis factor-. miR-223 controls the expression of fractalkine by targeting histone deacetylase 2. miR-223 levels are increased in COPD mouse models. miR-223 levels inversely correlate with HDAC2 expression in COPD patients. AbstractReduced activity of Histone Deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics.Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved i...

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Section: Introductionmentioning

confidence: 99%

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

et al. 2016

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“…Thus, increases or de novo induction of posttranslational histone modifications favorable to transcription (e.g., histone acetylation, and methylation of certain residues in histone H3) have been correlated with activation of IFN-␥ and the Th2 cytokine genes in Th1 and Th2 cells, respectively (27,28). There is little direct evidence about subsequent events at cytokine gene loci, these epigenetic modifications enhance the ability of proteins mediating gene transcription to access the promoter and increase rates of initiation at other genes (25,29,30). DNA methylation may serve as one means of repressing IFN-␥ expression in fully differentiated Th2 cells and, conversely, silencing the type 2 cytokine genes in Th1 cells (31)(32)(33).…”

mentioning

confidence: 99%

T-bet antagonizes mSin3a recruitment and transactivates a fully methylated IFN-γ promoter via a conserved T-box half-site

Ying-kai

Aune

Boothby

2005

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

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Promoter DNA methylation is a major epigenetic mechanism for silencing genes and establishing commitment in cells differentiating from their precursors. The transcription factor T-bet is a key determinant of IFN-␥ gene expression in helper T cells, but the mechanisms by which it achieves this effect are not clear. It is shown here that T-bet binds to a highly conserved T-box half-site in the IFN-␥ promoter, is recruited to the endogenous IFN-␥ promoter in T lymphoid cells, and transactivates gene expression through this sequence in a manner dependent on consensus T-box residues. This conserved promoter site is methylated in a model T cell line, and enforced T-bet expression did not alter its complete methylation. T-bet transactivated the conserved core promoter in transfection assays and collaborated functionally with C͞EBP␤ despite methylation of the conserved element. Importantly, enforced T-bet expression led to dissociation of the mSin3a corepressor from the endogenous, chromatinized IFN-␥ promoter without decreasing loading of the methyl-CpG binding protein MeCP2. These data indicate that T-bet can override repressive epigenetic modification by a mechanism in which this master regulator acts through a T-box half-site to enforce the activation of IFN-␥ gene expression in part by decreased loading of a corepressor on methylated DNA.corepressor ͉ DNA methylation ͉ transcription

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“…Binding of agonists induces release of repressor proteins and allows interaction with coactivators of the p160 class like SRC-1 or transcription intermediary factor 2 (TIF-2). These proteins have been shown to increase access to chromatin through acetylation of histones, mediate contact with general transcription factors, and enhance receptor AF-1͞AF-2 synergy (4,5).…”

mentioning

confidence: 99%

The basic helix–loop–helix–PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription

Brunnberg

Pettersson

Rydin

et al. 2003

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

124

112

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The biological effects of estrogens are mediated by the estrogen receptors ER␣ and ER␤. These receptors regulate gene expression through binding to DNA enhancer elements and subsequently recruiting factors such as coactivators that modulate their transcriptional activity. Here we show that ARNT (aryl hydrocarbon receptor nuclear translocator), the obligatory heterodimerization partner for the aryl hydrocarbon receptor and hypoxia inducible factor 1␣, functions as a potent coactivator of ER␣-and ER␤-dependent transcription. The coactivating effect of ARNT depends on physical interaction with the ERs and involves the C-terminal domain of ARNT and not the structurally conserved basic helixloop-helix and PAS (Per-ARNT-Sim) motifs. Moreover, we show that ARNT͞ER interaction requires the E2-activated ligand binding domain of ER␣ or ER␤. These observations, together with the previous role of ARNT as an obligatory partner protein for conditionally regulated basic helix-loop-helix-PAS proteins like the aryl hydrocarbon receptor or hypoxia inducible factor 1␣, expand the cellular functions of ARNT to include regulation of ER␣ and ER␤ transcriptional activity. ARNT was furthermore recruited to a natural ER target gene promoter in a estrogen-dependent manner, supporting a physiological role for ARNT as an ER coactivator.cross-talk ͉ chromatin immunoprecipitation E strogens regulate important physiological processes, such as development and function of the male and female reproductive system and maintenance of bone mass in women, and represent a protective factor against cardiovascular disease (1). The physiological effects of estrogens are mediated by estrogen receptors ␣ (ER␣) and ␤ (ER␤), which belong to the nuclear receptor superfamily (1, 2). Nuclear receptors are liganddependent transcription factors characterized by a conserved structural arrangement composed of a centrally located DNA binding domain (DBD) containing two highly conserved Zn finger motifs. This domain is flanked in the N terminus by a variable A͞B region, which contains an activation function (AF-1). The ligand binding domain (LBD), located C-terminally of the DBD, contains a second AF (AF-2) and is also responsible for ligand binding, receptor dimerization, and cofactor interaction (3).The ERs are, in the absence of ligand, present in the nucleus in a nonactivated form. The latent ERs interact with corepressors such as N-Cor, SHP, or SMRT, which inhibit constitutive transcriptional activity (1). Binding of agonists induces release of repressor proteins and allows interaction with coactivators of the p160 class like SRC-1 or transcription intermediary factor 2 (TIF-2). These proteins have been shown to increase access to chromatin through acetylation of histones, mediate contact with general transcription factors, and enhance receptor AF-1͞AF-2 synergy (4, 5).Interestingly, p160 coactivators share considerable sequence homology to basic helix-loop-helix (bHLH)-PAS (Per-ARNTSim) transcription factors. This family also includes factors such as the aryl h...

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Chromatin remodeling and transcriptional activation: the cast (in order of appearance)

Cited by 176 publications

References 151 publications

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

T-bet antagonizes mSin3a recruitment and transactivates a fully methylated IFN-γ promoter via a conserved T-box half-site

The basic helix–loop–helix–PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription

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