RNA-directed epigenetic silencing of Periostin inhibits cell motility

Lister, Nicholas C.; Clemson, Matthew; Morris, Kevin V.

doi:10.1098/rsos.140545

Cited by 5 publications

(4 citation statements)

References 48 publications

(90 reference statements)

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“…The effector siRNAs required to drive RNAi must be administered continuously to repress a therapeutic target gene. This is not the case with RNA-induced TGS, where stable, long-term, silencing can be achieved following a relatively short duration of promoter targeting with the siRNAs ( 19 , 20 , 97 – 100 ) or small antisense RNA ( 14 , 101 ). This is because the mode of action for the observed gene silencing is transcriptional and driven ultimately by epigenetic silencing ( 79 , 102 ) and not ‘slicing’ of the genes messenger RNA as is the case with RNAi.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional gene silencing in humans

Weinberg¹,

Morris²

2016

Nucleic Acids Res

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It has been over a decade since the first observation that small non-coding RNAs can functionally modulate epigenetic states in human cells to achieve functional transcriptional gene silencing (TGS). TGS is mechanistically distinct from the RNA interference (RNAi) gene-silencing pathway. TGS can result in long-term stable epigenetic modifications to gene expression that can be passed on to daughter cells during cell division, whereas RNAi does not. Early studies of TGS have been largely overlooked, overshadowed by subsequent discoveries of small RNA-directed post-TGS and RNAi. A reappraisal of early work has been brought about by recent findings in human cells where endogenous long non-coding RNAs function to regulate the epigenome. There are distinct and common overlaps between the proteins involved in small and long non-coding RNA transcriptional regulatory mechanisms, suggesting that the early studies using small non-coding RNAs to modulate transcription were making use of a previously unrecognized endogenous mechanism of RNA-directed gene regulation. Here we review how non-coding RNA plays a role in regulation of transcription and epigenetic gene silencing in human cells by revisiting these earlier studies and the mechanistic insights gained to date. We also provide a list of mammalian genes that have been shown to be transcriptionally regulated by non-coding RNAs. Lastly, we explore how TGS may serve as the basis for development of future therapeutic agents.

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Section: Introductionmentioning

confidence: 99%

Transcriptional gene silencing in humans

Weinberg¹,

Morris²

2016

Nucleic Acids Res

Self Cite

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“…Interestingly, proliferation‐related genes such as Chitinase 3 like 1 ( CHI3L1 ) and periostin ( POSTN ) were among these upregulated genes. CHI3L1 and POSTN have been extensively described in the literature to be involved in tumour proliferation especially epigenetic modification [34,35]. Moreover, public database (GEPIA) analysis of the TCGA human samples dataset revealed an upregulated expression of CHI3L1 and POSTN in glioma compared with the matched normal tissue, which also showed similar expression distribution with FABP7 expression (Fig.…”

Section: Resultsmentioning

confidence: 83%

“…FABP7‐OA‐mediated acetylation of H3K27 on the promoters of both genes was confirmed. In effect, CHI3L1 and POSTIN are well known in the literature to be involved in tumour proliferation especially epigenetic modification [34,35]. As increased transcription of these genes leads to an increase in the levels of their protein secretion, we evaluated the impact of their recombinant proteins on proliferation and observed a partial rescue of proliferation in OA‐treated FABP7‐KO cells.…”

Section: Discussionmentioning

confidence: 99%

Oleic acid‐bound FABP7 drives glioma cell proliferation through regulation of nuclear lipid droplet formation

et al. 2022

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Fatty acid‐binding protein 7 (FABP7), one of the fatty acid (FA) chaperones involved in the modulation of intracellular FA metabolism, is highly expressed in glioblastoma, and its expression is associated with decreased patients' prognosis. Previously, we demonstrated that FABP7 requires its binding partner to exert its function and that a mutation in the FA‐binding site of FABP7 affects tumour biology. Here, we explored the role of FA ligand binding for FABP7 function in tumour proliferation and examined the mechanism of FABP7 and ligand interaction in tumour biology. We discovered that among several FA treatment, oleic acid (OA) boosted cell proliferation of FABP7‐expressing cells. In turn, OA increased FABP7 nuclear localization, and the accumulation of FABP7–OA complex in the nucleus induced the formation of nuclear lipid droplet (nLD), as well as an increase in colocalization of nLD with promyelocytic leukaemia (PML) nuclear bodies. Furthermore, OA increased mRNA levels of proliferation‐related genes in FABP7‐expressing cells through histone acetylation. Interestingly, these OA‐boosted functions were abrogated in FABP7‐knockout cells and mutant FABP7‐overexpressing cells. Thus, our findings suggest that FABP7–OA intracellular interaction may modulate nLD formation and the epigenetic status thereby enhancing transcription of proliferation‐regulating genes, ultimately driving tumour cell proliferation.

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“…The role of periostin in metastasis is well established (reviewed by Ratajczak-Wielgomas and Dziegiel, 2015) [ 154 ]. In line with this, inhibition of periostin using promoter-directed small antisense non-coding RNAs in vitro prevented the exponential expansion and motility of tumor cells [ 155 ].…”

Section: The Use Of Aos To Target Expression Of Downstream Fibrotimentioning

confidence: 99%

Targeting TGFβ Signaling to Address Fibrosis Using Antisense Oligonucleotides

et al. 2018

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Fibrosis results from the excessive accumulation of extracellular matrix in chronically injured tissue. The fibrotic process is governed by crosstalk between many signaling pathways. The search for an effective treatment is further complicated by the fact that there is a degree of tissue-specificity in the pathways involved, although the process is not completely understood for all tissues. A plethora of drugs have shown promise in pre-clinical models, which is not always borne out translationally in clinical trial. With the recent approvals of two antisense oligonucleotides for the treatment of the genetic diseases Duchenne muscular dystrophy and spinal muscular atrophy, we explore here the potential of antisense oligonucleotides to knockdown the expression of pro-fibrotic proteins. We give an overview of the generalized fibrotic process, concentrating on key players and highlight where antisense oligonucleotides have been used effectively in cellular and animal models of different fibrotic conditions. Consideration is given to the advantages antisense oligonucleotides would have as an anti-fibrotic therapy alongside factors that would need to be addressed to improve efficacy. A prospective outlook for the development of antisense oligonucleotides to target fibrosis is outlined.

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RNA-directed epigenetic silencing of Periostin inhibits cell motility

Cited by 5 publications

References 48 publications

Transcriptional gene silencing in humans

Transcriptional gene silencing in humans

Oleic acid‐bound FABP7 drives glioma cell proliferation through regulation of nuclear lipid droplet formation

Targeting TGFβ Signaling to Address Fibrosis Using Antisense Oligonucleotides

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