• T32 DE017551 NIDCR NIH HHS
• F30 DE033286 NIDCR NIH HHS
• R21 CA246233 NCI NIH HHS
• R01 AI180047 NIAID NIH HHS
• I01 RX000444 RRD VA
• P30 CA138313 NCI NIH HHS
• R01 DK124553 NIDDK NIH HHS
• P20 GM130457 NIGMS NIH HHS
• R01 DK136658 NIDDK NIH HHS
• IK6 BX004858 BLRD VA
• P30 DK123704 NIDDK NIH HHS
• I01 BX003050 BLRD VA
• T32 DK124191 NIDDK NIH HHS
• R01 EY030072 NEI NIH HHS

• Biomechanics
• Molecular biology
• Molecular physiology
• Nucleic acids

• Actins/metabolism
• Actomyosin/metabolism
• Adherens Junctions/metabolism
• Cadherins/metabolism
• Cytokinesis
• Epithelial Cells/metabolism
• Nonmuscle Myosin Type IIB/metabolism
• Humans

• T32 DE017551 NIDCR NIH HHS
• P30 DK123704 NIDDK NIH HHS
• R21 CA246233 NCI NIH HHS
• P20 GM103499 NIGMS NIH HHS
• P30 CA138313 NCI NIH HHS
• R01 DK124553 NIDDK NIH HHS
• P20 GM130457 NIGMS NIH HHS
• TL1 TR001451 NCATS NIH HHS
• T32 DK124191 NIDDK NIH HHS
• UL1 TR001450 NCATS NIH HHS

• Molecular biology
• Omics

• R01 HL153915 NHLBI NIH HHS

• HIV-1 latent reservoir
• epigenetic silencing
• layer-by-layer
• poly-l-arginine
• siRNA delivery

• AGO2
• PSMC3
• RNAi
• USP14
• deubiquitination
• proteasome

• 3' Untranslated Regions/genetics
• Argonaute Proteins/genetics
• Argonaute Proteins/metabolism
• Cell Line, Tumor
• Eukaryotic Initiation Factors/genetics
• Eukaryotic Initiation Factors/metabolism
• Gene Expression Regulation
• HEK293 Cells
• Humans
• Interleukin-6/genetics
• Interleukin-6/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Molecular Chaperones/genetics
• Molecular Chaperones/metabolism
• Mutation
• Nuclear Pore Complex Proteins/genetics
• Nuclear Pore Complex Proteins/metabolism
• Pancreatitis, Acute Necrotizing/genetics
• Pancreatitis, Acute Necrotizing/metabolism
• Protein Binding
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Sumoylation

• FRN 102725 CIHR
• Canadian Institutes of Health Research
• Fujian Medical University
• Natural Sciences and Engineering Research Council of Canada

• Argonaute Proteins/genetics
• Cell Line
• Cell Line, Tumor
• Enhancer Elements, Genetic/genetics
• Estradiol/genetics
• Estrogens/genetics
• Eukaryotic Initiation Factors/genetics
• Gene Expression Regulation, Neoplastic/genetics
• HEK293 Cells
• Humans
• MCF-7 Cells
• Promoter Regions, Genetic/genetics
• Protein Binding/genetics
• Transcription Factors/genetics
• Transcription, Genetic/genetics
• Transcriptional Activation/genetics

• Howard Hughes Medical Institute

• HIV-1
• block and lock
• cure strategies
• epigenetic silencing
• latent reservoir

• CD4-Positive T-Lymphocytes
• HIV Infections/drug therapy
• HIV-1/genetics
• Humans
• Myeloid Cells
• Virus Latency
• Virus Replication

Here, we report novel tumour suppressor activity for the Drosophila Argonaute family RNA-binding protein AGO1, a component of the miRNA-dependent RNA-induced silencing complex (RISC). The mechanism for growth inhibition does not, however, involve canonical roles as part of the RISC; rather, AGO1 controls cell and tissue growth by functioning as a direct transcriptional repressor of the master regulator of growth, Myc. AGO1 depletion in wing imaginal discs drives a significant increase in ribosome biogenesis, nucleolar expansion and cell growth in a manner dependent on Myc abundance. Moreover, increased Myc promoter activity and elevated Myc mRNA in AGO1-depleted animals requires RNA polymerase II transcription. Further support for transcriptional AGO1 functions is provided by physical interaction with the RNA polymerase II transcriptional machinery (chromatin remodelling factors and Mediator Complex), punctate nuclear localisation in euchromatic regions and overlap with Polycomb Group transcriptional silencing loci. Moreover, significant AGO1 enrichment is observed on the Myc promoter and AGO1 interacts with the Myc transcriptional activator Psi. Together, our data show that Drosophila AGO1 functions outside of the RISC to repress Myc transcription and inhibit developmental cell and tissue growth.

This article has an associated ‘The people behind the papers’ interview.

Highlighted Article: In the Drosophila wing, the Argonaute family protein AGO1 acts independently of the miRNA-silencing pathway to restrict tissue growth by directly repressing transcription of the master growth regulator Myc.

• Argonaute
• Drosophila
• Myc
• Proliferation
• Psi
• Transcription

• Epigenetics
• History of epigenetics
• Integrative analysis

• CCR4-NOT
• PAR-CLIP
• RISC
• RNA binding protein
• deadenylation
• miRNA

• Animals
• Argonaute Proteins/genetics
• Argonaute Proteins/physiology
• Cell Differentiation/genetics
• Cell Line
• Cell Nucleus
• Cytoplasm
• Embryonic Stem Cells/metabolism
• Gene Silencing/physiology
• Humans
• Mammals
• Mice
• MicroRNAs/genetics
• MicroRNAs/physiology
• RNA Interference
• RNA Stability
• RNA, Messenger
• RNA, Small Interfering
• RNA-Binding Proteins
• RNA-Induced Silencing Complex/genetics
• RNA-Induced Silencing Complex/metabolism
• Transcription Factors

• Z99 AR999999 Intramural NIH HHS
• ZIA AR041200-01 Intramural NIH HHS

• chromatin
• lncRNA
• miRNA
• noncoding RNA
• piRNA
• siRNA
• transcriptional activation

• gap junctions
• intercellular communication
• intracellular transport
• miRNA translocation
• small RNA

• methionine cycle
• methionine salvage pathway
• methylthioadenosine phosphorylase
• polyamine metabolism
• prostate cancer

MicroRNAs (miRNAs) have been suggested to repress transcription via binding the 3′-untranslated regions of mRNAs. However, the involvement and details of miRNA-mediated epigenetic regulation, particularly in targeting genomic DNA and mediating epigenetic regulation, remain largely uninvestigated. In the present study, transcription factor CCAAT/enhancer binding protein delta (CEBPD) was responsive to the anticancer drug bortezomib, a clinical and highly selective drug for leukemia treatment, and contributed to bortezomib-induced cell death. Interestingly, following the identification of CEBPD-induced miRNAs, we found that miR-744, miR-3154 and miR-3162 could target CpG islands in the 5′-flanking region of the CEBPD gene. We previously demonstrated that the Yin Yang 1 (YY1)/polycomb group (PcG) protein/DNA methyltransferase (DNMT) complex is important for CCAAT/enhancer binding protein delta (CEBPD) gene inactivation; we further found that Argonaute 2 (Ago2) interacts with YY1 and binds to the CEBPD promoter. The miRNA/Ago2/YY1/PcG group protein/DNMT complex linked the inactivation of CEBPD and genes adjacent to its 5′-flanking region, including protein kinase DNA-activated catalytic polypeptide (PRKDC), minichromosome maintenance-deficient 4 (MCM4) and ubiquitin-conjugating enzyme E2 variant 2 (UBE2V2), upon bortezomib treatment. Moreover, we revealed that miRNA binding is necessary for YY1/PcG group protein/DNMT complex-mediated epigenetic gene silencing and is associated with bortezomib-induced methylation on genomic DNA. The present study successfully characterized the interactions of the miRNA/Ago2/YY1/PcG group protein/DNMT complex and provided new insights for miRNA-mediated epigenetic regulation in bortezomib-induced leukemic cell arrest and cell death.

• argonautes
• histone methylation
• live-cell imaging
• nuclear RNAi
• transcription

• Cell Nucleus/genetics
• DNA Methylation/drug effects
• Epigenesis, Genetic
• Gene Expression Regulation
• Green Fluorescent Proteins/analysis
• Green Fluorescent Proteins/genetics
• Green Fluorescent Proteins/metabolism
• HEK293 Cells
• Histone Methyltransferases
• Histone-Lysine N-Methyltransferase/antagonists & inhibitors
• Histone-Lysine N-Methyltransferase/genetics
• Histone-Lysine N-Methyltransferase/metabolism
• Humans
• In Situ Hybridization, Fluorescence/methods
• Microscopy, Fluorescence/methods
• Molecular Imaging/methods
• Piperazines/pharmacology
• Promoter Regions, Genetic
• Quinazolines/pharmacology
• RNA Interference
• RNA Precursors/genetics
• RNA, Small Interfering
• Transcription Initiation Site

In this study, we originally aimed to characterize the potential role of Argonaute 2 (AGO2) in the nucleus, a key protein of the miRNA machinery. We combined Chromatin Immunoprecipitation (ChIP) with high throughput sequencing (ChIP-seq) and quantitative mass spectrometry (ChIP-MS) using the broadly used AGO2 11A9 antibody to determine interactions with chromatin and nuclear proteins. We found a previously described interaction between AGO2 and SWI/SNF on chromatin with ChIP-MS and observed enrichment at enhancers and transcription start sites using ChIP-seq. However, antibody specificity issues can produce misleading results for ChIP, RNA-seq and Mass spectrometry. Therefore, we developed a CRISPR/Cas9 engineered AGO2^−/− HEK293T cell line to validate our findings. ChIP-qPCR and immunoprecipitation combined with MS (IP-MS) showed that the 11A9 antibody associates with chromatin and SWI/SNF in the absence of AGO2. Furthermore, stoichiometry, IP-MS and co-IP analysis suggests a direct interaction of this antibody with SMARCC1, a component of the SWI/SNF complex. For this reason, particular care should be taken in performing and interpreting experiments in which the 11A9 antibody is used to study a nuclear role of AGO2.

HIV-1 infection has been transformed by combined anti-retroviral therapy (ART), changing a universally fatal infection into a controllable infection. However, major obstacles for an HIV-1 cure exist. The HIV latent reservoir, which exists in resting CD4+ T cells, is not impacted by ART, and can reactivate when ART is interrupted or ceased. Additionally, multi-drug resistance can arise. One alternate approach to conventional HIV-1 drug treatment that is being explored involves gene therapies utilizing RNA-directed gene regulation. Commonly known as RNA interference (RNAi), short interfering RNA (siRNA) induce gene silencing in conserved biological pathways, which require a high degree of sequence specificity. This review will provide an overview of the silencing pathways, the current RNAi technologies being developed for HIV-1 gene therapy, current clinical trials, and the challenges faced in progressing these treatments into clinical trials.

• HIV-1
• RNAi
• clinical trials
• gene therapy
• transcriptional gene silencing

• Delivery
• Oligonucleotide therapeutics
• PNA
• PPMO
• miRNA
• siRNA

• epigenetics
• miRNA inducing silencing complex (miRISC)
• microRNA
• nuclear function
• transcriptional control

• Alternative Splicing
• Animals
• Cell Nucleolus/genetics
• Cell Nucleolus/metabolism
• Cytoplasm/genetics
• Cytoplasm/metabolism
• Gene Expression Regulation
• Humans
• MicroRNAs/analysis
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA Transport
• Transcriptome

• Animals
• Cell Line
• Epigenesis, Genetic
• Gene Silencing
• Humans
• Mammals/genetics
• Models, Biological
• RNA, Antisense/metabolism
• RNA, Long Noncoding/genetics
• Transcription, Genetic

• R01 AI111139 NIAID NIH HHS
• P01 AI099783 NIAID NIH HHS
• R01 CA151574 NCI NIH HHS
• R01 DK104681 NIDDK NIH HHS

• Argonaute
• Drosophila melanogaster
• Gene silencing
• Human
• Model organisms
• RNAi
• Small RNAs

• Ago2
• RNA-binding protein
• cervix
• keratinocyte
• keratinocytes
• microRNA (miRNA)
• microscopic imaging
• nuclear distribution
• papillomavirus
• virus

• 3' Untranslated Regions
• Argonaute Proteins/metabolism
• Cell Line
• ELAV-Like Protein 1/metabolism
• Gene Expression Regulation
• Humans
• MicroRNAs/metabolism
• RNA, Messenger/metabolism
• Ribonucleases/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• 1R21CA175794 NCI NIH HHS
• SC1GM083806 NIGMS NIH HHS

Transcriptional gene silencing (TGS) of mammalian genes can be induced by short interfering RNA (siRNA) targeting promoter regions. We previously reported potent TGS of HIV-1 by siRNA (PromA), which targets tandem NF-κB motifs within the viral 5′LTR. In this study, we screened a siRNA panel with the aim of identifying novel 5′LTR targets, to provide multiplexing potential with enhanced viral silencing and application toward developing alternate therapeutic strategies. Systematic examination identified a novel siRNA target, si143, confirmed to induce TGS as the silencing mechanism. TGS was prolonged with virus suppression >12 days, despite a limited ability to induce post- TGS. Epigenetic changes associated with silencing were suggested by partial reversal by histone deacetylase inhibitors and confirmed by chromatin immunoprecipitation analyses, which showed induction of H3K27me3 and H3K9me3, reduction in H3K9Ac, and recruitment of argonaute-1, all characteristic marks of heterochromatin and TGS. Together, these epigenetic changes mimic those associated with HIV-1 latency. Further, robust resistance to reactivation was observed in the J-Lat 9.2 cell latency model, when transduced with shPromA and/or sh143. These data support si/shRNA-mediated TGS approaches to HIV-1 and provide alternate targets to pursue a functional cure, whereby the viral reservoir is locked in latency following antiretroviral therapy cessation.

• Adenocarcinoma/genetics
• Adenocarcinoma of Lung
• Apoptosis
• Argonaute Proteins/genetics
• Eukaryotic Initiation Factors/genetics
• Gene Knockdown Techniques/methods
• Genetic Vectors/pharmacology
• HEK293 Cells
• HeLa Cells
• Humans
• Lentivirus/genetics
• Lung Neoplasms/genetics
• MicroRNAs/genetics
• Plasmids/genetics
• RNA Helicases
• RNA Precursors/genetics
• RNA, Antisense/genetics
• Trans-Activators/genetics

• Wellcome Trust
• 073980 Wellcome Trust
• 097945 Wellcome Trust
• G0801738 Medical Research Council

• HIV-1 transcription
• clinical trials
• gene therapy
• humanized mouse model
• latency
• non-coding RNA
• shRNA
• siRNA

While human immunodeficiency virus 1 (HIV-1) infection is controlled through continuous, life-long use of a combination of drugs targeting different steps of the virus cycle, HIV-1 is never completely eradicated from the body. Despite decades of research there is still no effective vaccine to prevent HIV-1 infection. Therefore, the possibility of an RNA interference (RNAi)-based cure has become an increasingly explored approach. Endogenous gene expression is controlled at both, transcriptional and post-transcriptional levels by non-coding RNAs, which act through diverse molecular mechanisms including RNAi. RNAi has the potential to control the turning on/off of specific genes through transcriptional gene silencing (TGS), as well as fine-tuning their expression through post-transcriptional gene silencing (PTGS). In this review we will describe in detail the canonical RNAi pathways for PTGS and TGS, the relationship of TGS with other silencing mechanisms and will discuss a variety of approaches developed to suppress HIV-1 via manipulation of RNAi. We will briefly compare RNAi strategies against other approaches developed to target the virus, highlighting their potential to overcome the major obstacle to finding a cure, which is the specific targeting of the HIV-1 reservoir within latently infected cells.

• Human immunodeficiency virus 1
• RNA interference
• Reservoirs
• Epigenetics
• Latency
• Transcriptional gene silencing
• Post-transcriptional gene silencing

Vascular endothelial growth factors (VEGFs) and their receptors (VEGF-R) are central regulators of vasculogenesis, angiogenesis, and lymphangiogenesis. They contribute to many vascular-related pathologies, and hence VEGF-targeted therapies have been widely sought after. In this study, the authors investigated the ability of promoter-targeted small hairpin RNAs (shRNAs) to regulate VEGF-A, VEGF-C and VEGF-R1 in different cell lines. The authors identified shRNAs that can upregulate hVEGF-C at both the mRNA and protein levels, and differentially regulate hVEGF-A depending on the cell type. Likewise, the authors identified shRNA that downregulated VEGF-R1 gene expression. Hence, promoter-targeted shRNAs can affect endogenous gene expression not only bimodally, but also differentially in a cell-type specific manner. Importantly, all three genes tested were regulated by at least one shRNA, supporting the idea that nuclear RNA interference is a widespread phenomenon. The level of regulation across the panel of shRNAs varied maximally from a 2.2-fold increase to a 4-fold decrease. This level of change should be useful in fine-tuning and modulating target gene expression, which for potent molecules, such as VEGF-A and VEGF-C, can be very beneficial. These promoter-targeted shRNAs may facilitate the design and development of targeted, context-dependent strategies for both pro- and antiangiogenic therapies for the treatment of vascular-related pathologies.

Alternative splicing is primarily controlled by the activity of splicing factors and by the elongation of the RNA polymerase II (RNAPII). Recent experiments have suggested a new complex network of splicing regulation involving chromatin, transcription and multiple protein factors. In particular, the CCCTC-binding factor (CTCF), the Argonaute protein AGO1, and members of the heterochromatin protein 1 (HP1) family have been implicated in the regulation of splicing associated with chromatin and the elongation of RNAPII. These results raise the question of whether these proteins may associate at the chromatin level to modulate alternative splicing.

Using chromatin immunoprecipitation sequencing (ChIP-Seq) data for CTCF, AGO1, HP1α, H3K27me3, H3K9me2, H3K36me3, RNAPII, total H3 and 5metC and alternative splicing arrays from two cell lines, we have analyzed the combinatorial code of their binding to chromatin in relation to the alternative splicing patterns between two cell lines, MCF7 and MCF10. Using Machine Learning techniques, we identified the changes in chromatin signals that are most significantly associated with splicing regulation between these two cell lines. Moreover, we have built a map of the chromatin signals on the pre-mRNA, that is, a chromatin-based RNA-map, which can explain 606 (68.55%) of the regulated events between MCF7 and MCF10. This chromatin code involves the presence of HP1α, CTCF, AGO1, RNAPII and histone marks around regulated exons and can differentiate patterns of skipping and inclusion. Additionally, we found a significant association of HP1α and CTCF activities around the regulated exons and a putative DNA binding site for HP1α.

Our results show that a considerable number of alternative splicing events could have a chromatin-dependent regulation involving the association of HP1α and CTCF near regulated exons. Additionally, we find further evidence for the involvement of HP1α and AGO1 in chromatin-related splicing regulation.

The online version of this article (doi:10.1186/s12915-015-0141-5) contains supplementary material, which is available to authorized users.

In spite of prolonged and intensive treatment with combined antiretroviral therapy (cART), which efficiently suppresses plasma viremia, the integrated provirus of HIV-1 persists in resting memory CD4⁺ T cells as latent infection. Treatment with cART does not substantially reduce the burden of latent infection. Once cART is ceased, HIV-1 replication recrudesces from these reservoirs in the overwhelming majority of patients. There is increasing evidence supporting a role for noncoding RNAs (ncRNA), including microRNAs (miRNAs), antisense (as)RNAs, and short interfering (si)RNA in the regulation of HIV-1 transcription. This appears to be mediated by interaction with the HIV-1 promoter region. Viral miRNAs have the potential to act as positive or negative regulators of HIV transcription. Moreover, inhibition of virally encoded long-asRNA can induce positive transcriptional regulation, while antisense strands of siRNA targeting the NF-κB region suppress viral transcription. An in-depth understanding of the interaction between ncRNAs and the HIV-1 U3 promoter region may lead to new approaches for the control of HIV reservoirs. This review focuses on promoter associated ncRNAs, with particular emphasis on their role in determining whether HIV-1 establishes active or latent infection.

Argonautes are highly conserved proteins found in almost all eukaryotes and some bacteria and archaea. In humans, there are eight argonaute proteins evenly distributed across two clades, the Ago clade (AGO1-4) and the Piwi clade (PIWIL1-4). The function of Ago proteins is best characterized by their role in RNA interference (RNAi) and cytoplasmic post-transcriptional gene silencing (PTGS) – which involves the loading of siRNA or miRNA into argonaute to direct silencing of genes at the posttranscriptional or translational level. However, nuclear-localized, as opposed to cytoplasmic, argonaute-small RNA complexes may also orchestrate the mechanistically very different process of transcriptional gene silencing, which results in prevention of transcription from a gene locus by the formation of silent chromatin domains. More recently, the role of argonaute in other aspects of epigenetic regulation of chromatin, alternative splicing and DNA repair is emerging. This review focuses on the activity of nuclear-localized short RNA-argonaute complexes in a mammalian setting and discusses recent in vivo studies employing nuclear-directed sRNA for therapeutic interventions. These studies heed the potential development of RNA-based drugs which induce epigenetic changes in the cell.

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.

• 5′UTR
• RNA activation
• coding sequence
• miRNA
• miRNA*
• non-canonical
• subcellular localization
• transcriptional silencing

MicroRNAs (miRNAs) are a class of genome-encoded small RNAs that are primarily considered to be post-transcriptional negative regulators of gene expression acting in the cytoplasm. Over a decade of research has focused on this canonical paradigm of miRNA function, with many success stories. Indeed, miRNAs have been identified that act as master regulators of a myriad of cellular processes, and many miRNAs are promising therapeutic targets or disease biomarkers. However, it is becoming increasingly apparent that the canonical view of miRNA function is incomplete. Several lines of evidence now point to additional functions for miRNAs in the nucleus of the mammalian cell. The majority of cellular miRNAs are present in both the nucleus and the cytoplasm, and certain miRNAs show specific nuclear enrichment. Additionally, some miRNAs colocalize with sub-nuclear structures such as the nucleolus and chromatin. Multiple components of the miRNA processing machinery are present in the nuclear compartment and are shuttled back and forth across the nuclear envelope. In the nucleus, miRNAs act to regulate the stability of nuclear transcripts, induce epigenetic alterations that either silence or activate transcription at specific gene promoters, and modulate cotranscriptional alternative splicing events. Nuclear miRNA-directed gene regulation constitutes a departure from the prevailing view of miRNA function and as such, warrants detailed further investigation.

• Argonaute
• RNA activation
• RNA interference
• Transcriptional regulation
• microRNA

• Argonaute proteins
• alternative splicing
• cancer
• histone modifications
• transcription regulation

• neurodegeneration
• gene therapy
• rna interference
• nanoparticles

• Blood-Brain Barrier/metabolism
• Drug Carriers/chemistry
• Genetic Vectors/metabolism
• Humans
• Nanoparticles/chemistry
• Nervous System Diseases/metabolism
• Nervous System Diseases/pathology
• Nervous System Diseases/therapy
• RNA Interference
• RNA, Small Interfering/administration & dosage
• Translational Research, Biomedical
• Viruses/genetics

MicroRNAs are key regulators of many biological processes, including cell differentiation. These small RNAs exert their function assembled in the RNA-induced silencing complexes (RISCs), where members of Argonaute (Ago) family of proteins provide a unique platform for target recognition and gene silencing. Here, by using myeloid cell lines and primary blasts, we show that Ago2 has a key role in human monocytic cell fate determination and in LPS-induced inflammatory response of 1,25-dihydroxyvitamin D₃ (D3)-treated myeloid cells. The silencing of Ago2 impairs the D3-dependent miR-17-5p/20a/106a, miR-125b and miR-155 downregulation, the accumulation of their translational targets AML1, VDR and C/EBPβ and monocytic cell differentiation. Moreover, we show that Ago2 is recruited on miR-155 host gene promoter and on the upstream region of an overlapping antisense lncRNA, determining their epigenetic silencing, and miR-155 downregulation. These findings highlight Ago2 as a new factor in myeloid cell fate determination in acute myeloid leukemia cells.