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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林劭品(Shau-Ping Lin) | |
| dc.contributor.author | Chih-Yun Yu | en |
| dc.contributor.author | 游芷芸 | zh_TW |
| dc.date.accessioned | 2021-06-17T01:34:40Z | - |
| dc.date.available | 2025-08-15 | |
| dc.date.copyright | 2020-08-24 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-15 | |
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The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell, 14(4), 644-658. doi:10.1111/acel.12344 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67494 | - |
| dc.description.abstract | 細胞增生與衰老之間的平衡，與器官生成、老化、再生醫學及癌症發生有密切關係。隨著細胞衰老，細胞核發生結構重整以及表觀基因體重塑，而衰老細胞中異染色質比例下降，會漸漸失去對反轉錄跳躍子的抑制。活化的反轉錄跳躍子將威脅基因體完整性。為維持細胞分裂複製基因模板的正確性，無法修復的細胞將進入「不分裂程序」，我們稱這樣的細胞作「殭屍細胞 (senescence cell)」。這些不分裂的殭屍細胞並未被修復，在被清除前仍為不穩定之存在。本研究中意外發現，表現外源類三號DNA甲基化因子(DNA methylatransferase 3-like,DNMT3L) 可以在分裂代數較晚的小鼠胚胎纖維母細胞 (mouse embryonic fibrobalsts, MEFs) 中，透過細胞核結構重整以及表觀基因修飾重塑，召集表觀基因調控蛋白以靜默跳躍子，顯著延緩老化的細胞進入不分裂程序。類三號DNA甲基化因子相對顯著表現於生殖細胞與幹細胞中，作用為協助抑制跳躍子及建立親緣特異性之基因組印痕標記。完整的DNMT3L蛋白在體細胞內難以測得存在。本研究發現僅需「暫時性」給予老化的小鼠纖維母細胞外源性DNMT3L即可修復大半老化細胞中監管異常的表觀基因，使整體基因表現趨勢相對受控。反觀現有的細胞抗老化研究模式：多強行使衰老細胞重新進入細胞周期，而未修復可能具癌化風險的老化表觀基因體，本研究利用表觀基因組及轉錄基因組的分析，解構DNMT3L造成抗老化現象之分子機轉，並鑑定參與抗老化的因子，提供一新穎的角度開發相對安全的抗老化因子─利用DNMT3L短暫表現模式，緩解基因體不穩定的危險因子，開啟抗老化相關研究的新方向並提供降低癌症的風險的線索，希冀在未來應用於開發老化相關疾病的預防及治療。 | zh_TW |
| dc.description.abstract | Loosening epigenetic control during cellular aging increases chromatin instability. To mitigate damage, cells with irreparable damage of all kinds would enter senescence. However, senescence only blocks cell proliferation for these damaged cells without fixing their aberrant chromatin signatures, which remain unstable and could be cancer-prone. As a serendipitous finding via studying retroviral silencing activities, we discovered that the transient ectopic expression of DNA methyltransferase 3-like (DNMT3L) was sufficient to drive late-passage mouse embryonic fibroblasts (MEFs) to halt senescence progression. DNMT3L promotes repression of some endogenous transposable elements and de-repressed coding genes in old MEFs. While DNMT3L repressed endogenous retroviruses by attracting H3K9me3 modification, the coding genes re-repressed in old MEFs by DNMT3L were mostly Polycomb Repressive Complex 2 (PRC2) targets in young MEFs. The up-regulation of those genes in old MEFs was associated with loss of the PRC2 mediated repressive mark, H3K27me3. After transient ectopic DNMT3L expression, a panel of PRC2 modulated genes regained repressive chromatin features. We demonstrated the interaction between DNMT3L and PRC2 in our system. Our data suggest that ectopic DNMT3L may guide PRC2 to redress certain loosened chromatin regions in aging cells. This study opens perspectives in the development of an epigenetic reinforcement strategy to overcome aging-associated epimutation and senescence. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T01:34:40Z (GMT). No. of bitstreams: 1 U0001-1508202017195300.pdf: 11378603 bytes, checksum: 4fd221708d8eb978bdeb12a87d5b1d08 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | Preface # 口試委員會審定書 # 誌謝 i 中文摘要 iii ABSTRACT iv TABLE OF CONTENTS v ABBREVIATIONS x LIST OF FIGURES xii Chapter 1 Introduction 1 1.1 Accumulation of senescent cells is a hallmark of aging 1 1.1.1 Senescent cells increase in aging tissue 1 1.1.2 Cellular senescence and aging-related diseases 2 1.1.3 Eliminating the senescent cells to extend healthspan 4 1.2 The trigger of cellular senescence 5 1.2.1 The limitation of cell-replication 5 1.2.2 Replicative senescence and replication-independent senescence 6 1.3 The global relaxation of chromatin before senescence 7 1.3.1 The re-organization of nuclear architecture during aging 7 1.3.2 Retrotransposons derepression during aging 8 1.4 Potential involvement of DNMT3L on tightening up relaxed chromatin structure 10 1.4.1 Ectopic DNMT3L triggers repressive chromatin modulators assembly against RTEs 10 1.4.2 Transient ectopic DNMT3L expression in late-passage MEFs induces long-term cell proliferation 11 Hypothesis 14 Significance 16 Chapter 2 Experimental design 18 2.1 Specific aim 1: To characterize cells after transient DNMT3L induction 18 2.1.1 Transcriptome analysis for genes after DNMT3L-pulse 18 2.1.2 Estimation of carcinogenesis potential for DNMT3L-treated MEFs 18 2.2 Specific aim 2: To investigate the mechanisms driving DNMT3L-treated MEFs to halt senescence progression 19 2.2.1 Establishment of doxycycline-inducible DNMT3L expression system in MEFs 19 2.2.2 Candidate approach for dissecting some of the protein compositions from ectopic DNMT3L triggered repression complex 20 2.2.3 To test the potential enrichment of repressive epigenetic chromatin marks on gene reigns potentially affected after DNMT3L pulse 20 2.3 Specific aim 3: Extended studies for the potential of DNMT3L-induced halting senescence ability in other somatic tissues 23 2.3.1 To generate dox-inducible tag-Dnmt3l expression transgenic mice 24 2.3.2 To observe the effect of DNMT3L pulse in other cell lineages 25 Chapter 3 Results 29 3.1 DNMT3L-treated MEFs changes in morphology and transformed into various shape in different culture media 29 3.2 Transcripts in DNMT3L-treated MEFs are more enriched in proliferative-categories 31 3.3 The gene expression pattern of DNMT3L-induced long-term proliferative MEFs are more similar to primary MEFs 35 3.4 A pulse of ectopic DNMT3L delays premature senescence in mouse embryonic fibroblasts 36 3.5 The DNMT3L-induced halting senescence machinery might be partly due to maintenance of the nuclear architecture. 41 3.6 A pulse of ectopic DNMT3L enhances long-lasting H3K9me3 on ERVs 43 3.7 DNMT3L treatment partly reverses aberrant gene expression after prolonged passages of cultured MEFs 45 3.8 DNMT3L enhances the repression of derepressed PRC2-targeted genes in old MEFs and globally reinforces H3K27me3 markers 46 3.9 Ectopic DNMT3L interacts with SUZ12 52 3.10 Ectopic DNMT3L restores H3K27me3 in the promoters of derepressed PRC2 target genes 55 Chapter 4 Discussion and conclusion 61 Chapter 5 Material and methods 73 5.1 Animal care and cell culture 73 5.2 Transient ectopic DNMT3L expression 73 5.3 Microarray analysis 73 5.4 Immunocytochemistry (ICC) 74 5.5 Western blotting (WB) 74 5.6 Chromatin immunoprecipitation (ChIP) 75 5.7 Viral‐mediated gene transfer 76 5.8 Immunoprecipitation (IP) 77 5.9 Total RNA extraction and RT-qPCR 77 5.10 Statistics analysis and graphical representation 78 References 80 Appendix 97 Plasmid map- pTRE-3G-BI-tag-mDNMT3L-GFP 98 Plasmid map- pTRE-3G-BI-Luciferase-GFP 99 Plasmid map- pEF1alpha-Tet3G 100 TetOn-DNMT3L is well-controlled by doxycycline induction 102 Plasmid set for Dox-inducible-D3L TG mice production 103 Preparation of pronuclear DNA microinjection 104 DNA fragments quality for pronuclear DNA microinjection 106 Genotyping results of Dox-tag D3L transgenic mice 108 Inducible mDnmt3l expression ES cell for blastocyst injection 111 Plasmid map-pAS4.1w.Ppuro-aOn (inducible lentiviral) 113 Plasmid map- pAS4.1w.Ppuro-aOn (Fasta Vector Sequence) 115 Plasmid map-pAS4.1wRFP-Control.Ppuro-aOn 120 Plasmid map-pMD2.G and psPAX2 (lentiviral packing) 121 Sequence for cloning: tag-mDnmt3l 122 Sequence for cloning: GFP 124 Figure S1 The transcriptome of DNMT3L-treated prolonged proliferative MEFs is still most similar to primary MEFs among the over 1000 cell types analyzed primary MEFs 125 Figure S2 DNMT3L-treated MEFs are more proliferative 126 Figure S3 Pairwise Spearman correlation matrix of genes in young, old and DNMT3L-treated MEFs 129 Figure S4 Gene ontology analysis of genes affected by DNMT3L-pulse 130 Figure S5 Overlapped DEGs among young, old and DNMT3L-treated MEFs 131 Figure S6 Grouping of genes affected by DNMT3L-pulse 132 Figure S7 The expression level of the potential regulators of genes affected by DNMT3L-pulse among young, old and DNMT3L-treated MEFs 134 Figure S8 The Doxycycline-inducible-DNMT3L-MEF expression system 135 Figure S9 The expression level of the repressive regulators assembled by ectopic DNMT3L among young, old and DNMT3L-treated MEFs 137 Figure S10 The relative expression of fibrosis-related genes 138 Table S1 The TE transcripts in Dnmt3l+/+ and Dnmt3l-/- MEFs 139 Table S2 Primer list 142 Short report for strand-specific RNA library construction 143 TrueSeq Strand-specific RNA library preparation 144 Sample note for TrueSeq 153 Quality control (QC) for TrueSeq 154 NET-seq subcellular fractionation protocol 155 Cellular fractionation optimization (for NET-seq preparation) 161 gRNA design for dCas9-KRAB transcriptional repression 165 gRNA oligo list (designed with DAN 2.0) 172 Guide RNA cloning map: pLX-sgRNA 173 pLX-sgRNA cloning plan 174 pLentiCRISPRv2 sgRNA cloning plan 175 pLentoCRISPRv2 protocol 176 Guide sequencing cloning protocol 177 Representative scientific artwork 178 Publication list 180 | |
| dc.language.iso | en | |
| dc.subject | 跳躍子 | zh_TW |
| dc.subject | 表觀基因體 | zh_TW |
| dc.subject | 細胞衰老 | zh_TW |
| dc.subject | 類三號DNA甲基化因子 | zh_TW |
| dc.subject | chromatin surveillance | en |
| dc.subject | Cellular senescence | en |
| dc.subject | epigenetics | en |
| dc.subject | DNMT3L | en |
| dc.subject | PRC2 | en |
| dc.title | 類3號DNA甲基化酶監管表觀基因體抵抗細胞衰老 | zh_TW |
| dc.title | DNMT3L Reinforces Chromatin Surveillance to Resist Senescence Progression | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.author-orcid | 0000-0002-0247-0503 | |
| dc.contributor.advisor-orcid | 林劭品(0000-0003-3423-991X) | |
| dc.contributor.oralexamcommittee | 蔡孟勲(Mong-Hsun Tsai),廖泰慶(Tai-Ching Liao),楊鎧鍵(Kai-Chien Yang),李宜靜(Yi-Ching Lee),張原翊(Yuan-I Chang) | |
| dc.subject.keyword | 細胞衰老,表觀基因體,跳躍子,類三號DNA甲基化因子, | zh_TW |
| dc.subject.keyword | Cellular senescence,epigenetics,DNMT3L,PRC2,chromatin surveillance, | en |
| dc.relation.page | 180 | |
| dc.identifier.doi | 10.6342/NTU202003530 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-08-17 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 生物科技研究所 | zh_TW |
| 顯示於系所單位： | 生物科技研究所 | |
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