Biaryl modification of the 5′-terminus of one strand of a microRNA duplex induces strand specificity

Ogata, Aya; Furukawa, Chihiro; Sakurai, Kouhei; Iba, Hideo; Kitade, Yukio; Ueno, Yoshihito

doi:10.1016/j.bmcl.2010.10.077

Cited by 20 publications

(9 citation statements)

References 15 publications

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“…In our previous studies using epithelial tumor cell lines, the d4-family members were shown to function as adaptor proteins linking the SWI/SNF complex with NF-κB dimers 15, 16 . Considering the rather strong dependency of GIC stemness maintenance on BRG1, DPF1 and DPF3a expression, we next tested whether SWI/SNF-dependent-NF-κB activation contributed to this biological activity.…”

Section: Resultsmentioning

confidence: 99%

“…By examining all of the d4-family proteins (DPF1, DPF2, DPF3a and DPF3b; a splicing variant of DPF3a), we further found that high level exogenous expression of each of these factors can potentiate the transactivating activity of typical NF-κB dimers including RelA/p50, which is responsible for the canonical NF-κB pathway, and RelB/p52, which is the most downstream factor of the non-canonical NF-κB pathway 16 . In addition, we demonstrated from our analysis in 293FT cells that DPF3a and 3b are the most effective cofactors of the SWI/SNF complex for RelA/p50 activation.…”

Section: Introductionmentioning

confidence: 88%

“…The pmU6 derivatives shCre#4 38 , shBrm#4 39 , shDPF1-CDS#1 16 and shDPF3a-3′UTR#2 16 were previously described. These pmU6-based plasmids were doubly digested with BamHI and EcoRI, and inserted into the same sites of pSSSP 40 , pSSCG 35 (EV-1) or pLE-IG (EV-2).…”

Section: Methodsmentioning

confidence: 99%

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The role of the SWI/SNF chromatin remodeling complex in maintaining the stemness of glioma initiating cells

Hiramatsu

Kobayashi

et al. 2017

Sci Rep

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Glioma initiating cells (GICs) are thought to contribute to therapeutic resistance and tumor recurrence in glioblastoma, a lethal primary brain tumor in adults. Although the stem-like properties of GICs, such as self-renewal and tumorigenicity, are epigenetically regulated, the role of a major chromatin remodeling complex in human, the SWI/SNF complex, remains unknown in these cells. We here demonstrate that the SWI/SNF core complex, that is associated with a unique corepressor complex through the d4-family proteins, DPF1 or DPF3a, plays essential roles in stemness maintenance in GICs. The seruminduced differentiation of GICs downregulated the endogenous expression of DPF1 and DPF3a, and the shRNA-mediated knockdown of each gene reduced both sphere-forming ability and tumor-forming activity in a mouse xenograft model. Rescue experiments revealed that DPF1 has dominant effects over DPF3a. Notably, whereas we have previously reported that d4-family members can function as adaptor proteins between the SWI/SNF complex and NF-κB dimers, this does not significantly contribute to maintaining the stemness properties of GICs. Instead, these proteins were found to link a corepressor complex containing the nuclear receptor, TLX, and LSD1/RCOR2 with the SWI/SNF core complex. Collectively, our results indicate that DPF1 and DPF3a are potential therapeutic targets for glioblastoma.Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults and remains incurable in spite of aggressive treatment approaches. A large body of evidence now indicates that stem-like cells, designated as glioma initiating cells (GICs), are thought to drive GBM propagation and cause therapeutic resistance in these tumors 1-3 . Chromatin structure modification has been shown to be an important determinant of GIC stemness maintenance as well as the induction of their differentiation 4,5 . Recently, using gene expression data from both stem-like and differentiated cell populations, it was shown that the simultaneous expression of four core transcription factors, POU3F2, SALL2, SOX2 and OLIG2, can reprogram differentiated GBM cells into spherogenic stem-like tumor-propagating cells 6 . These results demonstrate a plastic developmental hierarchy in GBM cell populations and reveal essential roles of epigenetic regulation in these biological processes 7 . In humans, the ATP-dependent chromatin remodeling factor, SWI/SNF complex, has been reported to play essential epigenetic roles in many biological processes [8][9][10] . As the catalytic subunit, each SWI/SNF complex has a single molecule of either BRG1 or Brm, but not both. The molecular components of these SWI/SNF complexes are now known to be highly polymorphic, in which some subunits that are encoded by homologous gene family members are integrated into the specific position of the complex in a mutually exclusive manner 8, 9, 11 . Importantly, exchange of a subunit with another family member has often been observed during several developmental processes within either the SWI/SNF core...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

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The role of the SWI/SNF chromatin remodeling complex in maintaining the stemness of glioma initiating cells

Hiramatsu

Kobayashi

et al. 2017

Sci Rep

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“…To identify the distinct mRNA targets of miR-199a-5p and -3p, we utilized our recently developed RNA duplex transfection technique. Using this method, we can selectively load miR-199a-5p or -3p onto an RNA-induced silencing complex (RISC), taking advantage of the phenomenon whereby chemical modification with 1-[3, 5-bis(hydroxymethyl)-phenyl]-4-(dimethylamino) naphthalene (DANap) on the 5 0 -end of one strand of the duplex supports only the selective loading of the unmodified strand onto RISCs in the transfected cells (28). In our current experiments, MDA-MB435 cells, which express marginal levels of endogenous miR-199a-5p/-3p, were transfected with 5p/ DANap-5os and 3p/DANap-3os to express exogenous miR199a-5p and miR-199a-3p, respectively ( Supplementary Fig.…”

Section: Thementioning

confidence: 99%

MicroRNAs miR-199a-5p and -3p Target the Brm Subunit of SWI/SNF to Generate a Double-Negative Feedback Loop in a Variety of Human Cancers

et al. 2011

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The chromatin remodeling complex SWI/SNF is an important epigenetic regulator that includes one Brm or BRG1 molecule as catalytic subunit. Brm and BRG1 do not function identically, so this complex can regulate gene expression either positively or negatively, depending on the promoter to which it is recruited. Notably, Brm attenuation due to posttranscription suppression occurs often in human tumor cells, in which this event contributes to their oncogenic potential. Here, we report that the 3 0 -untranslated region of Brm mRNA has two sites that are efficiently targeted by the microRNAs miR-199a-5p and -3p, revealing a novel mechanism for modulation of Brm-type SWI/SNF activity. Computational mapping of the putative promoter region of miR-199a-2 (miPPR-199a-2) has defined it as the major contributing genetic locus for miR-199a-5p and-3p production in these tumor cell lines. We validated this predicted region by direct promoter analysis to confirm that Egr1 is a strong positive regulator of the miR-199a-2 gene. Importantly, we also showed that Egr1, miR-199a-5p, and miR-199a-3p are expressed at high levels in Brm-deficient tumor cell lines but only marginally in Brm-expressing tumor cells. Finally, we also obtained evidence that Brm negatively regulates Egr1. Together, our results reveal that miR-199a and Brm form a double-negative feedback loop through Egr1, leading to the generation of these two distinct cell types during carcinogenesis. This mechanism may offer a partial explanation for why miR-199a-5p and -3p have been reported to be either upregulated or downregulated in a variety of tumors. Cancer Res; 71(5); 1680-9. Ó2010 AACR.

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“…The class of miRNA duplexes giving rise to balanced strand expression was termed “β-duplexes,” while the class of miRNA duplexes giving rise to a dominant strand was called “α-duplexes” (Kuchenbauer et al, 2011). Finally, these broader and evolutionary analyses are accompanied by reporter assays focusing on validating the miRNA ∗ functionality (Okamura et al, 2008; Ogata et al, 2010; Kuchenbauer et al, 2011; Yang et al, 2011; Byrd et al, 2012; Niederer et al, 2012; Chang et al, 2013; Goedeke et al, 2013; Martin et al, 2014). Altogether, these evidences suggest that all miRNA loci are potential dual-function genes, as two distinct miRNAs may originate from the same hairpin and, therefore, target different sets of genes (Okamura et al, 2008; Ogata et al, 2010; Ohanian et al, 2013).…”

Section: A Not So Passenger Strandmentioning

confidence: 99%

A non-canonical landscape of the microRNA system

Cipolla

2014

Front. Genet.

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Microribonucleic acids, best known as microRNAs or miRNAs, are small, non-coding RNAs with important regulatory roles in eukaryotic cells. Here, I present a broad review on highly relevant but generally non-depicted features of miRNAs, among which stand out the non-conventional miRNA seed sites, the unusual messenger RNA (mRNA) target regions, the non-canonical miRNA-guided mechanisms of gene expression regulation, and the recently identified new class of miRNA ligands. Furthermore, I address the miRNA uncommon genomic location, transcription, and subcellular localization. Altogether, these unusual features and roles place the miRNA system as a very diverse, complex, and intriguing biological mechanism.

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Biaryl modification of the 5′-terminus of one strand of a microRNA duplex induces strand specificity

Cited by 20 publications

References 15 publications

The role of the SWI/SNF chromatin remodeling complex in maintaining the stemness of glioma initiating cells

The role of the SWI/SNF chromatin remodeling complex in maintaining the stemness of glioma initiating cells

MicroRNAs miR-199a-5p and -3p Target the Brm Subunit of SWI/SNF to Generate a Double-Negative Feedback Loop in a Variety of Human Cancers

A non-canonical landscape of the microRNA system

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