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Implication des protéines HMGA et HMGA2 dans les changements du programme de réplication au cours de la sénescence cellulaire / HMGA proteins modify the replication program during senescenceKahli, Malik 20 September 2011 (has links)
La sénescence, considérée comme étant un arrêt irréversible du cycle cellulaire, se caractérise par des changements drastiques de l'expression génique et de l'organisation de la structure de la chromatine. En effet, il se forme des foyers denses d'hétérochromatine au sein du noyau (SAHF) et ces modifications s'accompagnent d'un déclin progressif de la capacité à dupliquer le génome. Au cours de ma thèse, j'ai voulu savoir si ces modifications de la chromatine induite par les SAHF pouvaient influer sur le programme de réplication et changer la distribution des origines de réplication sur le génome au cours du processus d'entrée en sénescence réplicative des cellules. Nous avons donc, dans un premier temps, comparé par peignage moléculaire de l'ADN réplicatif la distribution des origines de réplication de cellules primaires prolifératives et sénescentes. Nous avons également cartographié l'ensemble de leurs origines de réplication sur la totalité du génome en purifiant les brins naissants aux origines de réplication que nous avons couplé à une analyse de séquençage à haut débit.Les protéines HMGA1 et HMGA2 étant des éléments précurseurs essentiels à la mise en place des SAHF, nous avons créé des lignées cellulaires qui, en sur-exprimant de façon inductibles ces protéines, induit une sénescence prématurée. Nous avons réalisé le même type d'analyses sur ces cellules afin de mettre en évidence le rôle de ces protéines dans les modifications du programme de réplication que nous avons observé au cours de l'entrée en sénescence de ces différents types cellulaires. / Senescence, considered as an irreversible cell cycle arrest, is characterized by dramatic changes in genes expression and chromatin organisation forming dense heterochromatic foci (SAHF). These changes are concomitant to a progressive decline of the capactity to replicate the genome. My PhD topic was to investigate whether the chromatin changes induced by SAHF formation could influence the replication program and modify the origin distribution along the genome at replicative senescence. We first compared the origin distribution of proliferative and pre-senescent primary fibroblasts by DNA molecular combing. Then, we mapped the origins positions in whole human genome by using the nascent strand purification assay coupled to deep sequencing.As HMGA1 and HMGA2 proteins are essential to induce SAHF formation, we designed inducible cell lines wich overexpress these proteins, triggering premature senescence. We made the same type of experiments in these cell lines in order to investigate the implication of these proteins on the changes of the replication program we observed during senescence.
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Hes5 regulates the transition timing of neurogenesis and gliogenesis in mammalian neocortical development / 哺乳動物の大脳新皮質発生過程においてHes5はニューロン産生およびグリア産生の移行タイミングを制御するShama, Bansod 24 November 2017 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20756号 / 医博第4286号 / 新制||医||1024(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 伊佐 正, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Autonomous and non-autonomous regulation of chromatin structure during cellular senescenceParry, Aled John January 2018 (has links)
Senescent cells interact with the surrounding microenvironment achieving both pro- oncogenic and tumour-suppressive outcomes. In addition to autocrine and paracrine signalling mediated by factors of the senescence-associated secretory phenotype (SASP), we have recently identified that NOTCH1 can drive a unique form of senescence in adjacent cells via juxtacrine signalling. Here, we show that NOTCH1 signalling confers a dramatic impact on chromatin structure during senescence. RAS-induced senescent (RIS) fibroblasts often develop chromatin structures called senescence-associated heterochromatic foci (SAHF). We find that NOTCH1 inhibits SAHF formation at least partially through transcriptional repression of a critical structural component, high-mobility group A (HMGA). Using ATAC-sequencing (assay for transposase accessible chromatin) we demonstrate that nucleosome positioning is substantially altered in RIS and that this re-distribution is also antagonised by NOTCH1, resulting in a distinct chromatin landscape. Importantly, normal or cancer cells that express the NOTCH ligand jagged-1 can drive similar chromatin structural changes in adjacent cells in a cell-cell contact dependent manner. In addition, using a highly optimised chromatin immunoprecipitation (ChIP-seq) protocol and the proximity ligation assay ‘Hi-C’, we demonstrate that HMGA proteins are directly involved in the formation of long-range interactions in RIS cells that may underpin SAHF formation. These ChIP-seq data have also allowed us to identify a unique HMGA1 binding profile, potentially suggesting a novel role for HMGA1 in gene regulation. Together, our data indicate that NOTCH signalling, both cell-autonomously and non-cell-autonomously, can repress HMGA1, a multi-faceted protein that regulates nucleosome positioning (1D structure), SAHF formation (3D structure) and potentially mRNA abundance.
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Adenovirus Mediated Delivery of Decoy Hyper Binding Sites for Sequestration of an Oncogenic Transcription Factor HMGA as a Potential Novel Cancer Therapy and Antibacterial Activity of Local MushroomsHassan, Faizule 28 November 2017 (has links)
No description available.
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Development of DNA aptamer as a HMGA inhibitor for cancer therapy and NMR-based metabonomics studies in human/mouse cell linesWatanabe, Miki 05 December 2011 (has links)
No description available.
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