saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription

Portnoy, Victoria; Lin, Shin; Li, Kathy H.; Burlingame, Alma L.; Hu, Zhenghui; Li, Hao; Li, Long-Cheng

doi:10.1038/cr.2016.22

Cited by 102 publications

(107 citation statements)

References 79 publications

Supporting

Mentioning

104

Contrasting

Order By: Relevance

“…The active complex is guided to its target region by the guide strand, which may bind to complementary targets on either promoter DNA or nascent promoter RNA (9,27). A recent study also found the mechanism that saRNA-loaded Argonaut protein 2 facilitates the assembly of an RNA-induced transcriptional activation (RITA) complex, which interacts with RNA polymerase II to stimulate transcription initiation and productive elongation (29). In this study, fluorescently labeled dsRNA was used as a direct indicator of which strand can enter the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of E-cadherin by small activating RNA: A new double-stranded RNA

Wu¹,

Li²,

Li³

et al. 2016

International Journal of Oncology

View full text Add to dashboard Cite

Recent studies have reported that chemically synthesized small activating RNA (saRNA) targeting the promoter regions of a gene can activate its expression in different cell lines. This technique can be a powerful therapeutic method for diseases caused by complete inactivation or reduced expression of specific genes. E-cadherin is a typical tumor suppressor gene. Loss of E-cadherin mediates the transition from benign lesions to invasive, metastatic cancer. In this study, several 21-nt small double-stranded RNAs (dsRNAs) targeting the promoter regions of human E-cadherin were designed and synthesized and the features of their function were investigated to study the regulatory role of dsRNA on E-cadherin expression. A new saRNA (dsEcad‑661) that can enhance E-cadherin expression by targeting non-coding regulatory regions in gene promoters was identified. Using dsRNA with modified base quantity and cholesterol-conjugated dsRNA, we found the antisense strand may be the guide strand of saRNA in the upregulation of E-cadherin. These findings provide several important pieces of evidence that may improve understanding of the function of saRNA and may promote its development for clinical application.

show abstract

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of E-cadherin by small activating RNA: A new double-stranded RNA

Wu¹,

Li²,

Li³

et al. 2016

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…In a number of cases, Ago2 was reported to be the key player. It binds the target gene through saRNAs, it mediates the assembly of a supramolecular dock for RNApolII, and it is ultimately necessary for RNAa3550585960. Ago1 binds to TSS surroundings too.…”

Section: Discussionmentioning

confidence: 99%

RNA activation of haploinsufficient Foxg1 gene in murine neocortex

Fimiani

Goina

et al. 2016

Sci Rep

View full text Add to dashboard Cite

More than one hundred distinct gene hemizygosities are specifically linked to epilepsy, mental retardation, autism, schizophrenia and neuro-degeneration. Radical repair of these gene deficits via genome engineering is hardly feasible. The same applies to therapeutic stimulation of the spared allele by artificial transactivators. Small activating RNAs (saRNAs) offer an alternative, appealing approach. As a proof-of-principle, here we tested this approach on the Rett syndrome-linked, haploinsufficient, Foxg1 brain patterning gene. We selected a set of artificial small activating RNAs (saRNAs) upregulating it in neocortical precursors and their derivatives. Expression of these effectors achieved a robust biological outcome. saRNA-driven activation (RNAa) was limited to neural cells which normally express Foxg1 and did not hide endogenous gene tuning. saRNAs recognized target chromatin through a ncRNA stemming from it. Gene upregulation required Ago1 and was associated to RNApolII enrichment throughout the Foxg1 locus. Finally, saRNA delivery to murine neonatal brain replicated Foxg1-RNAa in vivo.

show abstract

“…It has been proposed that saRNAs may be involved in the regulation of the transcription elongation step through their interaction with Ago2 (ref. 42). Ago2, mostly known for its role in the RISC complex, can serve as an RNA-programmable homology search engine.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Oligonucleotide therapies for disorders of the nervous system

2017

View full text Add to dashboard Cite

Oligonucleotide therapies are currently experiencing a resurgence driven by advances in backbone chemistry and discoveries of novel therapeutic pathways that can be uniquely and efficiently modulated by the oligonucleotide drugs. A quarter of a century has passed since oligonucleotides were first applied in living mammalian brain to modulate gene expression. Despite challenges in delivery to the brain, multiple oligonucleotide-based compounds are now being developed for treatment of human brain disorders by direct delivery inside the blood brain barrier (BBB). Notably, the first new central nervous system (CNS)-targeted oligonucleotide-based drug (nusinersen/Spinraza) was approved by US Food and Drug Administration (FDA) in late 2016 and several other compounds are in advanced clinical trials. Human testing of brain-targeted oligonucleotides has highlighted unusual pharmacokinetic and pharmacodynamic properties of these compounds, including complex active uptake mechanisms, low systemic exposure, extremely long half-lives, accumulation and gradual release from subcellular depots. Further work on oligonucleotide uptake, development of formulations for delivery across the BBB and relevant disease biology studies are required for further optimization of the oligonucleotide drug development process for brain applications.

show abstract

saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription

Cited by 102 publications

References 79 publications

Transcriptional regulation of E-cadherin by small activating RNA: A new double-stranded RNA

Transcriptional regulation of E-cadherin by small activating RNA: A new double-stranded RNA

RNA activation of haploinsufficient Foxg1 gene in murine neocortex

Oligonucleotide therapies for disorders of the nervous system

Contact Info

Product

Resources

About