Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation

In the paper

“Under certain conditions, miRNAs can also activate translation or regulate transcription.”

What the sources say

• Not checked yetcites [16] Vasudevan, 2012, Posttranscriptional upregulation by microRNAs, Wiley Interdiscip Rev RNA source

In the paper

“The formation of a silencing miRISC complex starts with the recruitment of the GW182 family of proteins by miRISC; GW182 provides the scaffolding needed to recruit other effector proteins (52), such as the poly(A)-deadenylase complexes PAN2-PAN3 and CCR4-NOT, following miRNA:target mRNA interaction (50, 53).”

What the sources say

• Not checked yetcites [52] Behm-Ansmant, 2006, mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes, Genes Dev. source
• Not checked yetcites [50] Jonas, 2015, Towards a molecular understanding of microRNA-mediated gene silencing, Nat Rev Genet. source
• Not checked yetcites [53] Christie, 2013, Structure of the PAN3 pseudokinase reveals the basis for interactions with the PAN2 deadenylase and the GW182 proteins, Mol Cell. source

In the paper

“An example of such pre-miRNAs is mirtrons, which are produced from the introns of mRNA during splicing (35, 36).”

What the sources say

• Not checked yetcites [35] Ruby, 2007, Intronic microRNA precursors that bypass Drosha processing, Nature source
• Not checked yetcites [36] Babiarz, 2008, Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs, Genes Dev. source

In the paper

“On the other hand, Dicer-independent miRNAs are processed by Drosha from endogenous short hairpin RNA (shRNA) transcripts (38). These pre-miRNAs require AGO2 to complete their maturation within the cytoplasm because they are of insufficient length to be Dicer-substrates (38).”

What the sources say

• Not checked yetcites [38] Yang, 2010, Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis, Proc Natl Acad Sci USA. source

In the paper

“Several miRNAs, including let-7, were found to be associated with AGO2 and FXR1 to activate translation during cell cycle arrest, but they inhibit translation in proliferating cells (55).”

What the sources say

• Not checked yetcites [55] Vasudevan, 2007, AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2, Cell source

In the paper

“About half of all currently identified miRNAs are intragenic and processed mostly from introns and relatively few exons of protein coding genes, while the remaining are intergenic, transcribed independently of a host gene and regulated by their own promoters (13, 24).”

What the sources say

• Not checked yetcites [13] de Rie, 2017, An integrated expression atlas of miRNAs and their promoters in human and mouse, Nat Biotechnol. source
• Not checked yetcites [24] Kim, 2007, Processing of intronic microRNAs, EMBO J. source

In the paper

“The interaction of miRNAs with their target genes is dynamic and dependent on many factors, such as subcellular location of miRNAs, the abundancy of miRNAs and target mRNAs, and the affinity of miRNA-mRNA interactions.”

In the paper

“Once pre-miRNAs are generated, they are exported to the cytoplasm by an exportin 5 (XPO5)/RanGTP complex and then processed by the RNase III endonuclease Dicer (27, 30).”

What the sources say

• Not checked yetcites [27] Denli, 2004, Processing of primary microRNAs by the Microprocessor complex, Nature source
• Not checked yetcites [30] Okada, 2009, A high-resolution structure of the pre-microRNA nuclear export machinery, Science source

In the paper

“miRNAs are critical for normal animal development and are involved in a variety of biological processes (18).”

What the sources say

• Not checked yetcites [18] Fu, 2013, MicroRNAs in human placental development and pregnancy complications, Int J Mol Sci. source

In the paper

“miRNAs have also been shown to interact at genomic loci, where enhancer-derived RNA (eRNA) are transcribed, and increase mRNA levels of adjacent genes by promoting a transcriptionally active chromatin state (67) while altering alternative splicing profiles (64).”

What the sources say

• Not checked yetcites [67] Xiao, 2017, MicroRNAs activate gene transcription epigenetically as an enhancer trigger, RNA Biol. source
• Not checked yetcites [64] Allo, 2014, Argonaute-1 binds transcriptional enhancers and controls constitutive and alternative splicing in human cells, Proc Natl Acad Sci USA. source

In the paper

“Cooperation of multiple, proximal MREs on target mRNA has been shown to increase RNAi activity and increase retention times of miRISC complexes on those mRNA, most likely through the three AGO binding sites on the GW182 family proteins (94, 100).”

What the sources say

• Not checked yetcites [94] Denzler, 2016, Impact of MicroRNA levels, target-site complementarity, and cooperativity on competing endogenous RNA-regulated gene expression, Mol Cell source
• Not checked yetcites [100] Elkayam, 2017, Multivalent recruitment of human argonaute by GW182, Mol Cell. source

In the paper

“Alternative splicing and alternative polyadenylation affecting 3′ UTRs, and cell type-specific RNA binding proteins that affect target mRNA secondary structures, change the available pool of MREs (63, 68, 69).”

What the sources say

• Not checked yetcites [63] Bottini, 2017, Post-transcriptional gene silencing mediated by microRNAs is controlled by nucleoplasmic Sfpq, Nat Commun. source
• Not checked yetcites [68] Nam, 2014, Global analyses of the effect of different cellular contexts on microRNA targeting, Mol Cell. source
• Not checked yetcites [69] Blazie, 2017, Alternative polyadenylation directs tissue-specific miRNA targeting in Caenorhabditis elegans Somatic Tissues, Genetics source

In the paper

“Studies have revealed that miRNA-mediated gene regulation is dynamic and helps to buffer gene expression to a steady state.”

In the paper

“Nuclear localized miRISC was found to regulate both transcriptional rates and post-transcriptional levels of mRNA (59–61) and associate with euchromatin at gene loci with active transcription (62).”

What the sources say

• Not checked yetcites [59] Nishi, 2013, Human TNRC6A is an Argonaute-navigator protein for microRNA-mediated gene silencing in the nucleus, RNA source
• Not checked yetcites [60] Benhamed, 2012, Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells, Nat Cell Biol. source
• Not checked yetcites [61] Pitchiaya, 2017, Resolving subcellular miRNA trafficking and turnover at single-molecule resolution, Cell Rep. source
• Not checked yetcites [62] Cernilogar, 2011, Chromatin-associated RNA interference components contribute to transcriptional regulation in Drosophila, Nature source

In the paper

“Moreover, approximately half of the expressed miRNAs are cell type enriched, one quarter are broadly expressed, and the remaining had low-level expression regardless of cell type.”

What the sources say

• Not checked yetcites [13] de Rie, 2017, An integrated expression atlas of miRNAs and their promoters in human and mouse, Nat Biotechnol. source

In the paper

“miRISC has also been found to copurify with polysomes, and the miRISC:mRNA complexes bound to these polysomes were associated with increased levels of translational inhibition and mRNA degradation (83).”

What the sources say

• Not checked yetcites [83] Pillai, 2005, Inhibition of translational initiation by Let-7 MicroRNA in human cells, Science source

In the paper

“A recent study showed that miRNAs, AGO2, and target mRNAs are associated with rER-membrane-bound polysomes, and this occurs before miRNA-mediated translational repression (70).”

What the sources say

• Not checked yetcites [70] Barman, 2015, mRNA targeting to endoplasmic reticulum precedes ago protein interaction and microRNA (miRNA)-mediated translation repression in mammalian cells, J Biol Chem. source

In the paper

“For example, cyclin-dependent kinase inhibitor 1A (CDKN1A), a tumor suppressor that is downregulated in multiple cancers (106), is targeted by at least 28 miRNAs and many of which are upregulated together in cancers where CDKN1A has been implicated (107).”

What the sources say

• Not checked yetcites [106] Abbas, 2009, p21 in cancer: intricate networks and multiple activities, Nat Rev Cancer source
• Not checked yetcites [107] Wu, 2010, Multiple microRNAs modulate p21Cip1/Waf1 expression by directly targeting its 3′ untranslated region, Oncogene source

In the paper

“Additionally, the degree of polysome occupancy of target mRNAs is dependent on the affinity between miRNA seed region and MRE, but not on miRNA abundance (84).”

What the sources say

• Not checked yetcites [84] Molotski, 2012, Differential association of microRNAs with polysomes reflects distinct strengths of interactions with their mRNA targets, RNA source

In the paper

“The extracellular miRNAs can be delivered to target cells and they may act as autocrine, paracrine, and/or endocrine regulators to modulate cellular activities (116).”

What the sources say

• Not checked yetcites [116] Iftikhar, 2016, Evidence and potential in vivo functions for biofluid miRNAs: from expression profiling to functional testing: potential roles of extracellular miRNAs as indicators of physiological change and as agents of intercellular information exchange, Bioessays source

In the paper

“It has been shown that the secretion of exosomal miRNAs is mediated by a ceramide-dependent pathway and the secreted miRNAs exert growth regulatory effects in target cells (129).”

What the sources say

• Not checked yetcites [129] Kosaka, 2010, Secretory mechanisms and intercellular transfer of microRNAs in living cells, J Biol Chem. source

In the paper

“Both cell stress induced by heat shock and translation inhibition following treatment with hippuristanol or cycloheximide induced translocation of miRISC from the nucleus and cytoplasm to transient, cytoplasmic SG (72, 111).”

What the sources say

• Not checked yetcites [72] Detzer, 2011, Cell stress is related to re-localization of Argonaute 2 and to decreased RNA interference in human cells, Nucleic Acids Res. source
• Not checked yetcites [111] Leung, 2006, Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules, Proc Natl Acad Sci USA. source

In the paper

“While several studies found that the majority of extracellular miRNAs are not associated with exosomes/microvesicles but are instead bound to AGO2 (118, 125), another study reported that extracellular miRNAs are present predominantly in exosomes in human serum and saliva (120).”

What the sources say

• Not checked yetcites [118] Arroyo, 2011, Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma, Proc Natl Acad Sci USA source
• Not checked yetcites [125] Turchinovich, 2011, Characterization of extracellular circulating microRNA, Nucleic Acids Res. source

In the paper

“Extracellular miRNAs have also been reported to bind to Toll-like receptors (137), activate downstream signaling events, and eventually lead to biological responses, such as tumor growth and metastasis (138), and neurodegeneration (139).”

What the sources say

• Not checked yetcites [137] Fabbri, 2018, MicroRNAs and miRceptors: a new mechanism of action for intercellular communication, Philos Trans R Soc Lond B Biol Sci. source
• Not checked yetcites [138] Fabbri, 2012, MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response, Proc Natl Acad Sci USA. source
• Not checked yetcites [139] Lehmann, 2012, An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration, Nat Neurosci. source

In the paper

“For example, exosome mediated transfer of miR-105 from metastatic breast cancer cells to endothelial cells directly targeted a tight junction protein, zonula occludens 1 (ZO-1), and this led to the destruction of the barrier function of endothelium and promoted metastasis (134).”

What the sources say

• Not checked yetcites [134] Zhou, 2014, Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis, Cancer Cell source

In the paper

“The presence of miRNAs in vesicles or with accompanying proteins is generally thought to protect extracellular miRNAs and increase their stability in the extracellular milieu (120).”

What the sources say

• Not checked yetcites [120] Gallo, 2012, The majority of microRNAs detectable in serum and saliva is concentrated in exosomes, PLoS ONE source

In the paper

“This process has been reported to be dependent on clathrin, but not on caveolae or lipid rafts in PC12 cells (142).”

What the sources say

• Not checked yetcites [142] Tian, 2014, Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery, J Biol Chem. source

In the paper

“In neuroendocrine cells, miRNAs in large dense-core vesicles (LDCVs) are released by exocytosis through vesicle fusion, and this process is mediated by the SNARE complex and accelerated by Ca2+ stimulus (131).”

What the sources say

• Not checked yetcites [131] Gumurdu, 2017, MicroRNA exocytosis by large dense-core vesicle fusion, Sci Rep. source

In the paper

“another study reported that extracellular miRNAs are present predominantly in exosomes in human serum and saliva (120).”

What the sources say

• Not checked yetcites [120] Gallo, 2012, The majority of microRNAs detectable in serum and saliva is concentrated in exosomes, PLoS ONE source

In the paper

“Two populations of extracellular miRNAs exist in biological fluids. One can be found in vesicles such as exosomes, microvesicles, and apoptotic bodies (116, 120) while the other is associated with proteins, especially AGO2 (120, 125).”

What the sources say

• Not checked yetcites [116] Iftikhar, 2016, Evidence and potential in vivo functions for biofluid miRNAs: from expression profiling to functional testing: potential roles of extracellular miRNAs as indicators of physiological change and as agents of intercellular information exchange, Bioessays source
• Not checked yetcites [120] Gallo, 2012, The majority of microRNAs detectable in serum and saliva is concentrated in exosomes, PLoS ONE source
• Not checked yetcites [125] Turchinovich, 2011, Characterization of extracellular circulating microRNA, Nucleic Acids Res. source

In the paper

“Moreover, exosomes from umbilical cord blood were found to be enriched in miR-21-3p, which promoted the proliferation and migration of fibroblasts, and induced the angiogenic activities of endothelial cells, leading to accelerated wound healing (135).”

What the sources say

• Not checked yetcites [135] Hu, 2018, Exosomes from human umbilical cord blood accelerate cutaneous wound healing through miR-21-3p-mediated promotion of angiogenesis and fibroblast function, Theranostics source

In the paper

“In a study by Wang et al. (110), upon serum starvation of multiple human cell lines, there was an immediate exportation of stable, vesicular or vesicle-free miRNA and a concomitant decrease of intracellular miRNA levels (110).”

What the sources say

• Not checked yetcites [110] Wang, 2010, Export of microRNAs and microRNA-protective protein by mammalian cells, Nucleic Acids Res. source

In the paper

“Mechanisms by which miRNAs are secreted and taken up by cells are not well understood and require further investigation.”

In the paper

“It is now clear that miRNAs are powerful gene regulators, and that they not only help control mRNA stability and translation but are also involved in transcription.”

In the paper

“The assaying of miRNA activity within a test tube may not be recapitulated within the cellular environment and thus should be viewed with caution.”

In the paper

“Also, the addition of chemical tags to miRNA could also impact miRNA:MRE interaction or AGO:miRNA interactions, specifically with 5′ and 3′ miRNA nucleotide modifications.”

In the paper

“miRNAs regulate the activity of host cells, and they are also secreted and transferred to recipient cells.”

In the paper

“However, our understanding of when and how miRNAs can exert regulatory effects on transcription is limited.”

In the paper

“Many factors contribute to the activity of miRNAs, including subcellular location, miRNA/mRNA abundance, miRNA:MRE affinity, cell type/state, and the availability of various miRISC components.”

In the paper

“Cytosolic miRISC components shuttle between different compartments.”

In the paper

“However, most studies conducted so far were done in vitro using co-culture of different cell types.”

In the paper

“miRNAs in the nucleus play a role in regulating transcription and alternative splicing.”