Reprogrammable CRISPR/dCas9-based recruitment of DNMT1 for site-specific DNA demethylation and gene regulation

Lu, Anrui; Wang, Jingman; Sun, Wenjuan; Huang, Weiren; Cai, Zhiming; Zhao, Guoping; Wang, Jin

doi:10.1038/s41421-019-0090-1

Cited by 30 publications

(15 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bearing this in mind, Wang et al showed that pharmaceutical demethylation with 5-aza resulted in the upregulation of Klotho [47]. The results of this study support efforts to edit the methylation state of specific loci; recent advances in CRISPR-Cas9 technologies allow improved flexibility and specificity, modulated by single-guide RNA [150], facilitating active demethylation by employing the ten-eleven translocation (TET) family of methylcytosine dioxygenases [151][152][153][154][155][156][157][158][159]. These technological developments address ways in which methylation can be reversed and have the potential to provide a therapeutic advantage in tumours that display loss of Klotho protein expression.…”

Section: Therapeutic Approaches To Klotho Deliverysupporting

confidence: 67%

Klotho and the Treatment of Human Malignancies

Sachdeva

Gouge

Kontovounisios

et al. 2020

Cancers

View full text Add to dashboard Cite

Klotho was first discovered as an anti-ageing protein linked to a number of age-related disease processes, including cardiovascular, renal, musculoskeletal, and neurodegenerative conditions. Emerging research has also demonstrated a potential therapeutic role for Klotho in cancer biology, which is perhaps unsurprising given that cancer and ageing share similar molecular hallmarks. In addition to functioning as a tumour suppressor in numerous solid tumours and haematological malignancies, Klotho represents a candidate therapeutic target for patients with these diseases, the majority of whom have limited treatment options. Here, we examine contemporary evidence evaluating the anti-neoplastic effects of Klotho and describe the modulation of downstream oncogenic signalling pathways, including Wnt/β-catenin, FGF, IGF1, PIK3K/AKT, TGFβ, and the Unfolded Protein Response. We also discuss possible approaches to developing therapeutic Klotho and consider technological advances that may facilitate the delivery of Klotho through gene therapy.

show abstract

Section: Therapeutic Approaches To Klotho Deliverysupporting

confidence: 67%

Klotho and the Treatment of Human Malignancies

Sachdeva

Gouge

Kontovounisios

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…In addition, evolving gene editing approaches, including the use of nucleases such as TALENs (transcription activator-like effector nucleases), zinc-finger nucleases, and CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPRassociated 9) to instigate a sequence-specific change in the DNA [132][133][134], encouraged the development of gene expression regulation, epigenetic modification, functional gene screening, gene diagnosis, and therapeutic drug discovery [135][136][137][138][139][140]. For example, dCas9 can be fused with DNMTs or TETs to regulate DNA methylation, thereby regulating specific gene expression [141][142][143]. Similarly, dCas9 can be fused with HDACs or HATs to regulate chromatin structure, thereby regulating gene expression [144][145][146].…”

Section: Perspectives For Treatment and Prevention Of Neonatal Chronic Lung Diseasementioning

confidence: 99%

Intrauterine Hypoxia and Epigenetic Programming in Lung Development and Disease

et al. 2021

View full text Add to dashboard Cite

Clinically, intrauterine hypoxia is the foremost cause of perinatal morbidity and developmental plasticity in the fetus and newborn infant. Under hypoxia, deviations occur in the lung cell epigenome. Epigenetic mechanisms (e.g., DNA methylation, histone modification, and miRNA expression) control phenotypic programming and are associated with physiological responses and the risk of developmental disorders, such as bronchopulmonary dysplasia. This developmental disorder is the most frequent chronic pulmonary complication in preterm labor. The pathogenesis of this disease involves many factors, including aberrant oxygen conditions and mechanical ventilation-mediated lung injury, infection/inflammation, and epigenetic/genetic risk factors. This review is focused on various aspects related to intrauterine hypoxia and epigenetic programming in lung development and disease, summarizes our current knowledge of hypoxia-induced epigenetic programming and discusses potential therapeutic interventions for lung disease.

show abstract

“…48,49 dCas9-TET fusions have been used to demethylate the BRCA1 gene in vitro in MCF-7 and HeLa cells, upregulating BRCA1 expression and enhancing the cytotoxic effect of the chemotherapeutic Mitomycin-C. 49 Fusion of dCas9 with an R2-stemloop, a short RNA sequence that recruits the DNMT1 enzyme and inhibits its activity, has also shown potential as a demethylation strategy. 50 CRISPR/Cas9-mediated HDR can be used to correct small mutations, such as single nucleotide polymorphisms (SNPs) or indels, that knock out TSGs. The TP53 gene is estimated to be mutated in 30-35% of BCs and 80% of TNBCs.…”

Section: Targeting Oncogenes and Tsgsmentioning

confidence: 99%

Therapeutic applications of CRISPR/Cas9 in breast cancer and delivery potential of gold nanomaterials

Padayachee

Singh

2020

Nanobiomedicine

View full text Add to dashboard Cite

Globally, approximately 1 in 4 cancers in women are diagnosed as breast cancer (BC). Despite significant advances in the diagnosis and therapy BCs, many patients develop metastases or relapses. Hence, novel therapeutic strategies are required, that can selectively and efficiently kill malignant cells. Direct targeting of the genetic and epigenetic aberrations that occur in BC development is a promising strategy to overcome the limitations of current therapies, which target the tumour phenotype. The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system, composed of only an easily modifiable single guide RNA (sgRNA) sequence bound to a Cas9 nuclease, has revolutionised genome editing due to its simplicity and efficiency compared to earlier systems. CRISPR/Cas9 and its associated catalytically inactivated dCas9 variants facilitate the knockout of overexpressed genes, correction of mutations in inactivated genes, and reprogramming of the epigenetic landscape to impair BC growth. To achieve efficient genome editing in vivo, a vector is required to deliver the components to target cells. Gold nanomaterials, including gold nanoparticles and nanoclusters, display many advantageous characteristics that have facilitated their widespread use in theranostics, as delivery vehicles, and imaging and photothermal agents. This review highlights the therapeutic applications of CRISPR/Cas9 in treating BCs, and briefly describes gold nanomaterials and their potential in CRISPR/Cas9 delivery.

show abstract

Reprogrammable CRISPR/dCas9-based recruitment of DNMT1 for site-specific DNA demethylation and gene regulation

Cited by 30 publications

References 11 publications

Klotho and the Treatment of Human Malignancies

Klotho and the Treatment of Human Malignancies

Intrauterine Hypoxia and Epigenetic Programming in Lung Development and Disease

Therapeutic applications of CRISPR/Cas9 in breast cancer and delivery potential of gold nanomaterials

Contact Info

Product

Resources

About