Visualization of aging-associated chromatin alterations with an engineered TALE system

Ren, Rui; Deng, Liping; Xue, Yanhong; Suzuki, Keiichiro; Zhang, Weiqi; Yu, Yang; Wu, Jun; Sun, Liang; Gong, Xuejun; Luan, Huiqin; Yang, Fan; Ju, Zhenyu; Ren, Xiaoqing; Wang, Si; Tang, Hong; Geng, Li; Zhang, Weizhou; Li, Jian; Qiao, Jie; Xu, Tao; Qu, Jing; Liu, Guang Hui

doi:10.1038/cr.2017.18

Cited by 55 publications

(51 citation statements)

References 79 publications

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“…Cells derived from Bloom syndrome (mutated BLM) or Ataxia Telangiectasia (mutated ATM) patients show high variability of the rDNA copy number due to mitotic recombination in relation to their wild type counterparts [ 137 , 138 ]. Moreover, recent evidence suggests reduction of ribosomal DNA repeats as a trait of human aging [ 139 , 140 ]. Age-related neurological disorders, such as Hodgkin’s disease [ 141 ] and Parkinson’s disease [ 142 ], show deregulated rDNA transcription and nucleolar dysfunction.…”

Section: Rdna Damage and Disease Onsetmentioning

confidence: 99%

The Nucleolus: In Genome Maintenance and Repair

Tsekrekou

Stratigi

Chatzinikolaou

2017

IJMS

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Abstract:The nucleolus is the subnuclear membrane-less organelle where rRNA is transcribed and processed and ribosomal assembly occurs. During the last 20 years, however, the nucleolus has emerged as a multifunctional organelle, regulating processes that go well beyond its traditional role. Moreover, the unique organization of rDNA in tandem arrays and its unusually high transcription rates make it prone to unscheduled DNA recombination events and frequent RNA:DNA hybrids leading to DNA double strand breaks (DSBs). If not properly repaired, rDNA damage may contribute to premature disease onset and aging. Deregulation of ribosomal synthesis at any level from transcription and processing to ribosomal subunit assembly elicits a stress response and is also associated with disease onset. Here, we discuss how genome integrity is maintained within nucleoli and how such structures are functionally linked to nuclear DNA damage response and repair giving an emphasis on the newly emerging roles of the nucleolus in mammalian physiology and disease.

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Section: Rdna Damage and Disease Onsetmentioning

confidence: 99%

The Nucleolus: In Genome Maintenance and Repair

Tsekrekou

Stratigi

Chatzinikolaou

2017

IJMS

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“…Indeed, TALEs seemed to surpass the use of ZFPs because of their straightforward one-to-one binding approach. However, TALEs are quite big and the high number of repeats can cause assembly problems and aggregation [65], although the latter can be prevented by the fusion of thioredoxin [66].…”

Section: Second Generation: Protein-based Genetargeting Platforms (Zfmentioning

confidence: 99%

The past and presence of gene targeting: from chemicals and DNA via proteins to RNA

Geel

Ruiters

Cool

et al. 2018

Phil. Trans. R. Soc. B

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The ability to target DNA specifically at any given position within the genome allows many intriguing possibilities and has inspired scientists for decades. Early gene-targeting efforts exploited chemicals or DNA oligonucleotides to interfere with the DNA at a given location in order to inactivate a gene or to correct mutations. We here describe an example towards correcting a genetic mutation underlying Pompe's disease using a nucleotide-fused nuclease (TFO-MunI). In addition to the promise of gene correction, scientists soon realized that genes could be inactivated or even re-activated without inducing potentially harmful DNA damage by targeting transcriptional modulators to a particular gene. However, it proved difficult to fuse protein effector domains to the first generation of programmable DNA-binding agents. The engineering of gene-targeting proteins (zinc finger proteins (ZFPs), transcription activator-like effectors (TALEs)) circumvented this problem. The disadvantage of protein-based gene targeting is that a fusion protein needs to be engineered for every locus. The recent introduction of CRISPR/Cas offers a flexible approach to target a (fusion) protein to the locus of interest using cheap designer RNA molecules. Many research groups now exploit this platform and the first human clinical trials have been initiated: CRISPR/Cas has kicked off a new era of gene targeting and is revolutionizing biomedical sciences.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

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“…Spätere Experimente zeigten, dass Fusionen von ZFs und TALEs mit GFP so programmiert werden konnten, dass sie repetitive DNA‐Elemente wie z. B. Telomere und Centromere abbilden . Unglücklicherweise erwies sich die Bildgebung von nicht‐repetitiven genomischen Regionen mit ZFs und TALEs als weniger handhabbar.…”

Section: Bildgebung Von Genomenunclassified

Genome im Fokus: Entwicklung und Anwendungen von CRISPR‐Cas9‐Bildgebungstechnologien

2018

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Die Entdeckung der CRISPR‐Cas9‐Endonuklease ermöglicht die einfache Genom‐Editierung von lebenden Zellen und Organismen. Katalytisch deaktivierte Cas9 (dCas9) behält die Fähigkeit, DNA in einer RNA‐abhängigen Weise zu binden, und wurde zusätzlich als ein Werkzeug für die Transkriptionsmodulation, die Epigenom‐Editierung und die genomische Bildgebung entwickelt. Dieser Aufsatz zeigt die jüngsten Fortschritte und Herausforderungen bei der Entwicklung von dCas9 für die Bildgebung genomischer Loci auf. Die Entstehung und Weiterentwicklung dieser Technologie bietet das Potenzial, neue mechanistische Fragen über die Chromosomendynamik und die dreidimensionale Genomorganisation in vivo zu beantworten.

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Visualization of aging-associated chromatin alterations with an engineered TALE system

Cited by 55 publications

References 79 publications

The Nucleolus: In Genome Maintenance and Repair

The Nucleolus: In Genome Maintenance and Repair

The past and presence of gene targeting: from chemicals and DNA via proteins to RNA

Genome im Fokus: Entwicklung und Anwendungen von CRISPR‐Cas9‐Bildgebungstechnologien

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