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Identification of Novel Target Genes of the PTH-Activated NACA Transcriptional Coregulator in Bone.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Identification of Novel Target Genes of the PTH-Activated NACA Transcriptional Coregulator in Bone./
作者:	Hariri, Hadla M.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	231 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-10, Section: B.
Contained By:	Dissertations Abstracts International82-10B.
標題:	Cancer. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28383673
ISBN:	9798708715609

Identification of Novel Target Genes of the PTH-Activated NACA Transcriptional Coregulator in Bone.
Hariri, Hadla M.

Identification of Novel Target Genes of the PTH-Activated NACA Transcriptional Coregulator in Bone. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 231 p.

Source: Dissertations Abstracts International, Volume: 82-10, Section: B.

Thesis (Ph.D.)--McGill University (Canada), 2020.

This item must not be sold to any third party vendors.

The daily injection of parathyroid hormone (PTH) increases bone mass and protectsagainst osteoporotic fractures, however a complete picture of its mechanism of action is stillmissing. We have shown that PTH induces the phosphorylation of the DNA-binding proteinNascent polypeptide associated complex And Coregulator alpha (NACA), leading to nucleartranslocation of NACA and activation of target genes. We performed ChromatinImmunoprecipitation with deep sequencing (ChIP-Seq) against NACA with parallel RNAsequencingin PTH-treated osteoblast cells. This approach illuminated two novel downstreamtargets of the PTH-NACA axis in osteoblasts: the nuclear factor interleukin-3-regulated (Nfil3)and the ubiquitin specific peptidase 53 (Usp53). Our data show that the transcriptional activityof Nfil3 is activated by the binding of NACA and CREB to its proximal promoter, followingPTH induction. Additionally, our differentiation assays of Nfil3-knockdown cells reveal adistinct function for Nfil3 in osteoblasts vs osteocytes, by modulating their differentiation inopposing fashions. Our results serve as the first mechanistic characterization of Nfil3transcription and function in osteoblasts. Moreover, our work identified Usp53 as a novel targetof PTH signaling in osteoblasts and uncovered a mechanism involving NACA,JUN, and CREBtuning its transcription. A great deal of our work focused on uncovering the biological functionof Usp53 during development. We show here that USP 53 regulates mesenchymal cell lineageselection in vitro and in vivo. The phenotypic characterization of Usp53 null mice revealssevere alterations in bone and adipose tissues. The global ablation of Usp53 leads to low bonemass due to increased osteoclastogenesis and impairs adipogenesis. We also show that Usp53regulates adipogenic commitment and differentiation of mesenchymal cells, osteoblast terminaldifferentiation, and Rankl expression. The underlying mechanism defining Usp53 functionsinvolves the interaction with the TAK1/TAB1/TAB2 complex affecting its assembly andsignaling. This is the first study uncovering the contribution of Usp53 to developmentalprocesses and revealing the molecular cascades underlying Usp53-related pathologies inhuman. Collectively, the characterization of Nfil3 and Usp53 has proven that their biologicalsignificance extends beyond PTH signaling regulation to cover crucial developmental processesin multiple tissues.

ISBN: 9798708715609Subjects--Topical Terms:

634186
Cancer.
Subjects--Index Terms:

Novel target genes

Identification of Novel Target Genes of the PTH-Activated NACA Transcriptional Coregulator in Bone.
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500 $a Advisor: St-Arnaud, Rene.
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520 $a The daily injection of parathyroid hormone (PTH) increases bone mass and protectsagainst osteoporotic fractures, however a complete picture of its mechanism of action is stillmissing. We have shown that PTH induces the phosphorylation of the DNA-binding proteinNascent polypeptide associated complex And Coregulator alpha (NACA), leading to nucleartranslocation of NACA and activation of target genes. We performed ChromatinImmunoprecipitation with deep sequencing (ChIP-Seq) against NACA with parallel RNAsequencingin PTH-treated osteoblast cells. This approach illuminated two novel downstreamtargets of the PTH-NACA axis in osteoblasts: the nuclear factor interleukin-3-regulated (Nfil3)and the ubiquitin specific peptidase 53 (Usp53). Our data show that the transcriptional activityof Nfil3 is activated by the binding of NACA and CREB to its proximal promoter, followingPTH induction. Additionally, our differentiation assays of Nfil3-knockdown cells reveal adistinct function for Nfil3 in osteoblasts vs osteocytes, by modulating their differentiation inopposing fashions. Our results serve as the first mechanistic characterization of Nfil3transcription and function in osteoblasts. Moreover, our work identified Usp53 as a novel targetof PTH signaling in osteoblasts and uncovered a mechanism involving NACA,JUN, and CREBtuning its transcription. A great deal of our work focused on uncovering the biological functionof Usp53 during development. We show here that USP 53 regulates mesenchymal cell lineageselection in vitro and in vivo. The phenotypic characterization of Usp53 null mice revealssevere alterations in bone and adipose tissues. The global ablation of Usp53 leads to low bonemass due to increased osteoclastogenesis and impairs adipogenesis. We also show that Usp53regulates adipogenic commitment and differentiation of mesenchymal cells, osteoblast terminaldifferentiation, and Rankl expression. The underlying mechanism defining Usp53 functionsinvolves the interaction with the TAK1/TAB1/TAB2 complex affecting its assembly andsignaling. This is the first study uncovering the contribution of Usp53 to developmentalprocesses and revealing the molecular cascades underlying Usp53-related pathologies inhuman. Collectively, the characterization of Nfil3 and Usp53 has proven that their biologicalsignificance extends beyond PTH signaling regulation to cover crucial developmental processesin multiple tissues.
520 $a L'injection quotidienne d'hormone parathyroidienne (PTH) augmente la masse osseuse etprotege contre les fractures osteoporotiques. Cependant, le mecanisme d'action n'est pascompletement elucide. Nous avons demontre que la PTH induit la phosphorylation d'uneproteine qui se lie a l'ADN, le complexe associe au polypeptide naissant et coregulateur alpha(NACA). Ceci entraine la translocation nucleaire de NACA et l'activation de genes cibles. Nousavons effectue une immunoprecipitation de la chromatine avec un sequencage en profondeur(ChIP-Seq) contre le NACA ainsi qu'en parallele, un sequencage de l'ARN (RNA-Seq)d'osteoblastes traites a la PTH. Cette approche a permis d'identifier deux nouvelles cibles enaval de l'axe PTH-NACA dans les osteoblastes : le facteur nucleaire regule par l'interleukine-3(Nfil3) et la peptidase 53 specifique de l'ubiquitine (Usp53). Ensuite, nous avons demontre quel'activite transcriptionnelle de Nfil3 est activee par la liaison de NACA et de CREB a sonpromoteur proximal, en reponse a la PTH. De plus, nos tests de differenciation dans des cellulesdeficientes en Nfil3 suggerent que cette proteine a une fonction distincte dans les osteoblastescomparativement aux osteocytes et module leur differenciation de maniere opposee. Nosresultats sont les premiers a caracteriser le mecanisme de transcription et la fonction de Nfil3dans les osteoblastes. La deuxieme cible identifiee de la signalisation de PTH dans lesosteoblastes est l'Usp53. Nous avons decouvert que sa transcription est regulee par unmecanisme impliquant NACA, JUN et CREB. Nous nous sommes particulierement interesses aelucider le role de Usp53 durant le developpement embryologique. Nous montrons ici que l'Usp53 regule la selection de la lignee de cellules souches mesenchymateuses in vitro et in vivo.Ensuite, la caracterisation phenotypique des souris deficientes en Usp53 revele des changementsimportants au niveau des tissus osseux et adipeux. L'ablation globale de l'Usp53 alterel'adipogenese et entraine une faible masse osseuse suite a une osteoclastogenese augmentee.Nous montrons egalement que Usp53 regule la differenciation des cellules souchesmesenchymateuses en adipocytes, la differenciation terminale des osteoblastes et l'expression de Rankl. La fonction de Usp53 depend etroitement de son interaction avec le complexeTAK1/TAB1/TAB2, en modulant son assemblage et sa signalisation. Cette these est la premiereetude a decouvrir la contribution d'Usp53 aux processus developpementaux. Elle revele aussi lescascades moleculaires sous-jacentes aux pathologies liees a Usp53 chez l'homme.Collectivement, la caracterisation de Nfil3 et Usp53 a prouve que leur importance biologiqueviii s'etend au-dela de la regulation de la signalisation de la PTH et englobe des processusdeveloppementaux cruciaux dans de multiples tissus.
590 $a School code: 0781.
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650 4 $a Gene expression. $3 643979
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650 4 $a Physiology. $3 518431
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653 $a Novel target genes
653 $a PTH-activated
653 $a NACA transcriptional coregulator
653 $a Bone
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710 2 $a McGill University (Canada). $3 1018122
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