Combinatorial Targeting by MicroRNAs Co-ordinates Post-transcriptional Control of EMT

Cursons, Joseph; Pillman, Katherine A.; Scheer, Kaitlin G.; Gregory, Philip A.; Foroutan, Momeneh; Hediyeh-Zadeh, Soroor; Toubia, John; Crampin, Edmund J.; Goodall, Gregory J.; Bracken, Cameron P.; Davis, Melissa J.

doi:10.1016/j.cels.2018.05.019

Cited by 89 publications

(92 citation statements)

References 76 publications

(80 reference statements)

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“…Combinations of small RNAs (siRNAs or miRs) have been shown to improve cell proliferation, 14 and alter cellular phenotypes. 13 We thus hypothesized that MkMP-induced Mk differentiation of CD34 + HSPCs might be mediated by miR-486-5p and miR-22-3p acting together. We thus examined their combinatorial targeting on CD41 + or CD42b + expression, Mkcell count, and total cell count in TPO-free cultures post transfection of CD34 + cells.…”

Section: Mir-486-5p In Combination With Mir-22-3p Largely Recapitulatmentioning

confidence: 99%

“…There is increasing evidence however that two or more miRs are involved in co-regulating the same biological program or process in cancer 11,12 and normophysiology. 13 Combinations of miRs have been also used synthetically to regulate biological processes. 13,14 However, cooperation between miRs from an EV has been rarely examined.…”

Section: Introductionmentioning

confidence: 99%

“…13 Combinations of miRs have been also used synthetically to regulate biological processes. 13,14 However, cooperation between miRs from an EV has been rarely examined. Recently, Xu et al reported that a group of EV-associated miRs likely mediates pro-inflammatory cytokine production in a murine sepsis model, 15 but mechanistic understanding was not pursued.…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial effect of miR-486-5p & miR-22-3p mimics thrombopoietin's impact on hematopoietic stem & progenitor cells

Kao

Jiang

Papoutsakis

2020

Preprint

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Word Count (Text): 5429 Word Count (Abstract): 246 Figure Count: 7Table Count: 2 Reference Count: 61 Key Points• miR-486-5p and miR-22-3p drive megakaryocytic differentiation in the absence of thrombopoietin.• Megakaryocytic microparticles trigger megakaryocytic differentiation of CD34 + cells through JNK and PI3K/Akt/mTOR signaling. AbstractMegakaryocytes shed and release submicron size microparticles (MkMPs), the most abundant microparticle in circulation. We have previously reported that MkMPs target peripheral-blood CD34 + hematopoietic stem/progenitor cells (HSPCs) to induce megakaryocytic differentiation and proliferation, and that small RNAs delivered to HSPCs via MkMPs play an important role in the development of this phenotype. Here, using single-molecule real-time (SMRT) RNA sequencing (RNAseq), we identify the top seven most abundant microRNAs (miRs) in MkMPs as potential candidates in mediating the effect of MkMPs on HSPCs. Using miR mimics, we demonstrate that among the seven most abundant miRs, two, miR-486-5p and miR-22-3p, are able to drive the Mk differentiation of HSPCs in the absence of thrombopoietin (TPO). The effect of these two miRs is comparable to the TPO-or MkMP-induced megakaryocytic differentiation of HSPCs, thus suggesting that these two miRs are responsible for this MkMPinduced phenotype. To probe the signaling through which MkMPs might enable this phenotype, we used kinase inhibitors of potential signaling pathways engaged in megakaryocytic differentiation. Our data suggest that MkMP-induced Mk differentiation of HSPCs is enabled through JNK and PI3K/Akt/mTOR signaling. Our data show that MkMPs activate Akt and mTOR phosphorylation. Furthermore, MkMPs downregulate PTEN expression, a direct target of miR-486-5p and a negative regulator of PI3K/Akt signaling, via JNK signaling. Taken together, our data provide a mechanistic understanding of the biological effect of MkMPs in inducing megakaryocytic differentiation of HSPCs, which, as was previously suggested, is a phenotype of potential physiological significance in stress megakaryopoiesis.

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Section: Mir-486-5p In Combination With Mir-22-3p Largely Recapitulatmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combinatorial effect of miR-486-5p & miR-22-3p mimics thrombopoietin's impact on hematopoietic stem & progenitor cells

Kao

Jiang

Papoutsakis

2020

Preprint

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“…In this paper, we introduce the concept of "driver gene group", which is a set of genes that work in concert to regulate cancer or cancer markers. There is evidence showing that genes work together to regulate the same targets and the regulation of individual genes might not have significant impacts (Cursons et al, 2018;Karim et al, 2016). Furthermore, researchers have started to conduct wet-lab experiments to investigate the regulation by groups of genes in biological processes (Cursons et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…There is evidence showing that genes work together to regulate the same targets and the regulation of individual genes might not have significant impacts (Cursons et al, 2018;Karim et al, 2016). Furthermore, researchers have started to conduct wet-lab experiments to investigate the regulation by groups of genes in biological processes (Cursons et al, 2018). All of these highlight the importance of studying biological components working in groups, including groups of cancer drivers which collaboratively regulate targets to drive cancer.…”

Section: Introductionmentioning

confidence: 99%

DriverGroup: A novel method for identifying driver gene groups

Pham

Liu

Bracken

et al. 2020

Preprint

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Motivation:Identifying cancer driver genes is a key task in cancer informatics. Most exisiting methods are focused on individual cancer drivers which regulate biological processes leading to cancer. However, the effect of a single gene may not be sufficient to drive cancer progression. Here, we hypothesise that there are driver gene groups that work in concert to regulate cancer and we develop a novel computational method to detect those driver gene groups. Results: We develop a novel method named DriverGroup to detect driver gene groups by using gene expression and gene interaction data. The proposed method has three stages: (1) Constructing the gene network, (2) Discovering critical nodes of the constructed network, and (3) Identifying driver gene groups based on the discovered critical nodes. Before evaluating the performance of DriverGroup in detecting cancer driver groups, we firstly assess its performance in detecting the influence of gene groups, a key step of DriverGroup. The application of DriverGroup to DREAM4 data demonstrates that it is more effective than other methods in detecting the regulation of gene groups. We then apply DriverGroup to the BRCA dataset to identify coding and non-coding driver groups for breast cancer. The identified driver groups are promising as several group members are confirmed to be related to cancer in literature. We further use the predicted driver groups in survival analysis and the results show that the survival curves of patient subpopulations classified using the predicted driver groups are significantly differentiated, indicating the usefulness of DriverGroup.

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Synthetic Epigenetic Reprogramming of Mesenchymal to Epithelial States Using the CRISPR/dCas9 Platform in Triple Negative Breast Cancer

et al. 2023

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Epithelial-mesenchymal transition (EMT) is a reversible transcriptional program invoked by cancer cells to drive cancer progression.Transcription factor ZEB1 is a master regulator of EMT, driving disease recurrence in poor-outcome triple negative breast cancers (TNBCs). Here, this work silences ZEB1 in TNBC models by CRISPR/dCas9-mediated epigenetic editing, resulting in highly-specific and nearly complete suppression of ZEB1 in vivo, accompanied by long-lasting tumor inhibition. Integrated "omic" changes promoted by dCas9 linked to the KRAB domain (dCas9-KRAB) enabled the discovery of a ZEB1-dependent-signature of 26 genes differentially-expressed and -methylated, including the reactivation and enhanced chromatin accessibility in cell adhesion loci, outlining epigenetic reprogramming toward a more epithelial state. In the ZEB1 locus transcriptional silencing is associated with induction of locally-spread heterochromatin, significant changes in DNA methylation at specific CpGs, gain of H3K9me3, and a near complete erasure of H3K4me3 in the ZEB1 promoter. Epigenetic shifts induced by ZEB1-silencing are enriched in a subset of human breast tumors, illuminating a clinically-relevant hybrid-like state. Thus, the synthetic epi-silencing of ZEB1 induces stable "lock-in" epigenetic reprogramming of mesenchymal tumors associated with a distinct and stable epigenetic landscape. This work outlines epigenome-engineering approaches for reversing EMT and customizable precision molecular oncology approaches for targeting poor outcome breast cancers.

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Combinatorial Targeting by MicroRNAs Co-ordinates Post-transcriptional Control of EMT

Cited by 89 publications

References 76 publications

Combinatorial effect of miR-486-5p & miR-22-3p mimics thrombopoietin's impact on hematopoietic stem & progenitor cells

Combinatorial effect of miR-486-5p & miR-22-3p mimics thrombopoietin's impact on hematopoietic stem & progenitor cells

DriverGroup: A novel method for identifying driver gene groups

Synthetic Epigenetic Reprogramming of Mesenchymal to Epithelial States Using the CRISPR/dCas9 Platform in Triple Negative Breast Cancer

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