Glutamine-Expanded Ataxin-7 Alters TFTC/STAGA Recruitment and Chromatin Structure Leading to Photoreceptor Dysfunction

Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that theSCA7 gene product, ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase–containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function

Lestaurtinib Inhibits Histone Phosphorylation and Androgen-Dependent Gene Expression in Prostate Cancer Cells

Background: Epigenetics is defined as heritable changes in gene expression that are not based on changes in the DNA sequence. Posttranslational modification of histone proteins is a major mechanism of epigenetic regulation. The kinase PRK1 (protein kinase C related kinase 1, also known as PKN1) phosphorylates histone H3 at threonine 11 and is involved in the regulation of androgen receptor signalling. Thus, it has been identified as a novel drug target but little is known about PRK1 inhibitors and consequences of its inhibition. Methodology/Principal Finding: Using a focused library screening approach, we identified the clinical candidate lestaurtinib (also known as CEP-701) as a new inhibitor of PRK1. Based on a generated 3D model of the PRK1 kinase using the homolog PKC-theta (protein kinase c theta) protein as a template, the key interaction of lestaurtinib with PRK1 was analyzed by means of molecular docking studies. Furthermore, the effects on histone H3 threonine phosphorylation and androgen-dependent gene expression was evaluated in prostate cancer cells. Conclusions/Significance: Lestaurtinib inhibits PRK1 very potently in vitro and in vivo. Applied to cell culture it inhibits histone H3 threonine phosphorylation and androgen-dependent gene expression, a feature that has not been known yet. Thus our findings have implication both for understanding of the clinical activity of lestaurtinib as well as for future PRK

Characterization of a conformation of the histone H3 N-terminal tail modified in mitosis and study of the post-translational modifications of the transcription factor TAF10,two mechanisms involved in the regulation of gene expression

Mon travail a permis de révéler que TAF10, une sous-unité du facteur général de transcription TFIID mais aussi du complexe TFTC, est la cible de plusieurs modifications post-traductionnelles in vivo. En outre, la nature de ces modifications et/ou leur quantité varient suivant l'étape du cycle cellulaire dans laquelle est la cellule et le complexe où se trouve TAF10. Par ailleurs, les modifications post-traductionnelles ont également lieu sur les queues d'histones où elles sont des acteurs essentiels dans les mécanismes de condensation / décondensation de la chromatine. En caractérisant un anticorps spécifique de la mitose, appelé 51TA2H12, nous avons pu identifier, sur certaines régions de la chromatine, une conformation étirée des queues d'histones H3 diméthylées sur la lysine 9 et/ou 27 et phosphorylées sur la sérine 10 et/ou 28 (H3Kme2Sp). Des résultats préliminaires suggèrent une implication des queues d'histones H3Kme2Sp structurées dans le bon déroulement de la mitose.My work revealed that TAF10, a subunit of the general transcription factor TFIID but also of the TFTC complex, is the target of a number of post-translational modifications in vivo. Moreover, the type of these modifications and their ratio changes relatively to the phase of the cell cycle and the complex in which TAF10 is found. Furthermore, post-translational modifications also occur on histone tails, where they are essential players in condensation / decondensation mechanisms of the chromatin. By caractherizing a mitosis specific antibody, called 51TA2H12, we identified, on some regions of the chromatin, an elongated conformation of histone H3 tails dimethylated on lysine 9 and/or 27 and phosphorylated on serine 10 and/or 28 (H3Kme2Sp). Preliminary results suggest an ivolvement of H3Kme2Sp structured histone tails throughout mitosis

Characterization of a conformation of the histone H3 N-terminal tail modified in mitosis and study of the post-translational modifications of the transcription factor TAF10,two mechanisms involved in the regulation of gene expression

Mon travail a permis de révéler que TAF10, une sous-unité du facteur général de transcription TFIID mais aussi du complexe TFTC, est la cible de plusieurs modifications post-traductionnelles in vivo. En outre, la nature de ces modifications et/ou leur quantité varient suivant l'étape du cycle cellulaire dans laquelle est la cellule et le complexe où se trouve TAF10. Par ailleurs, les modifications post-traductionnelles ont également lieu sur les queues d'histones où elles sont des acteurs essentiels dans les mécanismes de condensation / décondensation de la chromatine. En caractérisant un anticorps spécifique de la mitose, appelé 51TA2H12, nous avons pu identifier, sur certaines régions de la chromatine, une conformation étirée des queues d'histones H3 diméthylées sur la lysine 9 et/ou 27 et phosphorylées sur la sérine 10 et/ou 28 (H3Kme2Sp). Des résultats préliminaires suggèrent une implication des queues d'histones H3Kme2Sp structurées dans le bon déroulement de la mitose.My work revealed that TAF10, a subunit of the general transcription factor TFIID but also of the TFTC complex, is the target of a number of post-translational modifications in vivo. Moreover, the type of these modifications and their ratio changes relatively to the phase of the cell cycle and the complex in which TAF10 is found. Furthermore, post-translational modifications also occur on histone tails, where they are essential players in condensation / decondensation mechanisms of the chromatin. By caractherizing a mitosis specific antibody, called 51TA2H12, we identified, on some regions of the chromatin, an elongated conformation of histone H3 tails dimethylated on lysine 9 and/or 27 and phosphorylated on serine 10 and/or 28 (H3Kme2Sp). Preliminary results suggest an ivolvement of H3Kme2Sp structured histone tails throughout mitosis

Characterization of a conformation of the histone H3 N-terminal tail modified in mitosis and study of the post-translational modifications of the transcription factor TAF10,two mechanisms involved in the regulation of gene expression

Mon travail a permis de révéler que TAF10, une sous-unité du facteur général de transcription TFIID mais aussi du complexe TFTC, est la cible de plusieurs modifications post-traductionnelles in vivo. En outre, la nature de ces modifications et/ou leur quantité varient suivant l'étape du cycle cellulaire dans laquelle est la cellule et le complexe où se trouve TAF10. Par ailleurs, les modifications post-traductionnelles ont également lieu sur les queues d'histones où elles sont des acteurs essentiels dans les mécanismes de condensation / décondensation de la chromatine. En caractérisant un anticorps spécifique de la mitose, appelé 51TA2H12, nous avons pu identifier, sur certaines régions de la chromatine, une conformation étirée des queues d'histones H3 diméthylées sur la lysine 9 et/ou 27 et phosphorylées sur la sérine 10 et/ou 28 (H3Kme2Sp). Des résultats préliminaires suggèrent une implication des queues d'histones H3Kme2Sp structurées dans le bon déroulement de la mitose.My work revealed that TAF10, a subunit of the general transcription factor TFIID but also of the TFTC complex, is the target of a number of post-translational modifications in vivo. Moreover, the type of these modifications and their ratio changes relatively to the phase of the cell cycle and the complex in which TAF10 is found. Furthermore, post-translational modifications also occur on histone tails, where they are essential players in condensation / decondensation mechanisms of the chromatin. By caractherizing a mitosis specific antibody, called 51TA2H12, we identified, on some regions of the chromatin, an elongated conformation of histone H3 tails dimethylated on lysine 9 and/or 27 and phosphorylated on serine 10 and/or 28 (H3Kme2Sp). Preliminary results suggest an ivolvement of H3Kme2Sp structured histone tails throughout mitosis

Characterization of a conformation of the histone H3 N-terminal tail modified in mitosis and study of the post-translational modifications of the transcription factor TAF10,two mechanisms involved in the regulation of gene expression

Mon travail a permis de révéler que TAF10, une sous-unité du facteur général de transcription TFIID mais aussi du complexe TFTC, est la cible de plusieurs modifications post-traductionnelles in vivo. En outre, la nature de ces modifications et/ou leur quantité varient suivant l'étape du cycle cellulaire dans laquelle est la cellule et le complexe où se trouve TAF10. Par ailleurs, les modifications post-traductionnelles ont également lieu sur les queues d'histones où elles sont des acteurs essentiels dans les mécanismes de condensation / décondensation de la chromatine. En caractérisant un anticorps spécifique de la mitose, appelé 51TA2H12, nous avons pu identifier, sur certaines régions de la chromatine, une conformation étirée des queues d'histones H3 diméthylées sur la lysine 9 et/ou 27 et phosphorylées sur la sérine 10 et/ou 28 (H3Kme2Sp). Des résultats préliminaires suggèrent une implication des queues d'histones H3Kme2Sp structurées dans le bon déroulement de la mitose.My work revealed that TAF10, a subunit of the general transcription factor TFIID but also of the TFTC complex, is the target of a number of post-translational modifications in vivo. Moreover, the type of these modifications and their ratio changes relatively to the phase of the cell cycle and the complex in which TAF10 is found. Furthermore, post-translational modifications also occur on histone tails, where they are essential players in condensation / decondensation mechanisms of the chromatin. By caractherizing a mitosis specific antibody, called 51TA2H12, we identified, on some regions of the chromatin, an elongated conformation of histone H3 tails dimethylated on lysine 9 and/or 27 and phosphorylated on serine 10 and/or 28 (H3Kme2Sp). Preliminary results suggest an ivolvement of H3Kme2Sp structured histone tails throughout mitosis

Caractérisation d'une conformation de la queue N-terminale de l'histoire H3 modifiée en mitose et étude des modifications post-traductionnelles du facteur de transcription TAF10 (deux mécanismes impliqués dans la régulation de l'expression des gènes)

Mon travail a permis de révéler que TAF10, une sous-unité du facteur général de transcription TFIID mais aussi du complexe TFTC, est la cible de plusieurs modifications post-traductionnelles in vivo. En outre, la nature de ces modifications et/ou leur quantité varient suivant l étape du cycle cellulaire dans laquelle est la cellule et le complexe où se trouve TAF10. Par ailleurs, les modifications post-traductionnelles ont également lieu sur les queues d histones où elles sont des acteurs essentiels dans les mécanismes de condensation / décondensation de la chromatine. En caractérisant un anticorps spécifique de la mitose, appelé 51TA2H12, nous avons pu identifier, sur certaines régions de la chromatine, une conformation étirée des queues d histones H3 diméthylées sur la lysine 9 et/ou 27 et phosphorylées sur la sérine 10 et/ou 28 (H3Kme2Sp). Des résultats préliminaires suggèrent une implication des queues d histones H3Kme2Sp structurées dans le bon déroulement de la mitose.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Acyl derivatives of p-aminosulfonamides and dapsone as new inhibitors of the arginine methyltransferase hPRMT1

Arginine methylation is an epigenetic modification that receives increasing interest as it plays an important role in several diseases. This is especially true for hormone-dependent cancer, seeing that histone methylation by arginine methyltransferase I (PRMT1) is involved in the activation of sexual hormone receptors. Therefore, PRMT inhibitors are potential drugs and interesting tools for cell biology. A dapsone derivative called allantodapsone previously identified by our group served as a lead structure for inhibitor synthesis. Acylated derivatives of p-aminobenzenesulfonamides and the antilepra drug dapsone were identified as new inhibitors of PRMT1 by in vitro testing. The bis-chloroacetyl amide of dapsone selectively inhibited human PRMT1 in the low micromolar region and was selective for PRMT1 as compared to the arginine methyltransferase CARM1 and the lysine methyltransferase Set7/9. It showed anticancer activity on MCF7a and LNCaP cells and blocked androgen dependent transcription specifically in a reporter gene system. Likewise, a transcriptional block was also demonstrated in LNCaP cells using quantitative RT-PCR on the mRNA of androgen dependent genes

Known and newly identified PRK1 inhibitors.

<p>Known and newly identified PRK1 inhibitors.</p