Regulation of mammalian microrna expression springerlink. The properties of a cell are determined by the genetic information encoded in its genome. Sep 25, 2012 micrornas mirnas are small noncoding rnas that regulate expression of various target genes. Plant micrornas in crosskingdom regulation of gene. The expression of various genes are regulated by micrornas, and several micrornas act in reciprocal negative feedback loops with protein factors to control cell fate decisions that are triggered by signal transduction activity. Micrornamediated regulation is a key component in a wide range of biological processes such as stem cell maintenance, developmental timing, metabolism, hostviral interaction, apoptosis, cardiac and skeletal muscle proliferation 1 and neuronal gene expression 2. Intronic micrornas support their host genes by mediating. Identifying expression patterns of mirnas in copd may enhance our understanding of the mechanisms of disease.
Micrornas are a family of small, noncoding rnas that regulate gene expression in a sequencespecific manner. Here, a new class of rnabased switches is described. Jun 27, 2012 regulation of mammalian gene expression by exogenous micrornas hongwei liang jiangsu engineering research center for microrna biology and biotechnology, state key laboratory of pharmaceutical biotechnology, school of life sciences, nanjing university, nanjing, china. Reversible gene regulation in mammalian cells using.
Micrornas mirnas, are usually around 20 nucleotide bases long the building blocks of dna and rna and repress gene expression by basepairing to mrnas. Epigenetic alterations such as dna methylation and histone modification are essential for chromatin remodeling and regulation of gene. Biogenesis and regulation of cardiovascular micrornas. Gene regulatory factors that control the expression of genomic information come in a variety of. Transcriptional co regulation of micrornas and proteincoding genes. A first regulatory step in the biogenesis of mirnas occurs at the level of transcription. Although recent advances have been made in identifying and analyzing instances of micrornamediated gene regulation, it remains unclear by what mechanisms attenuation of transcript expression through micrornas becomes an integral part of posttranscriptional modification, and it is even less clear to what extent this process occurs for mammalian gene duplicates paralogs. Preferential regulation of duplicated genes by micrornas. Role of ctcf in the regulation of microrna expression. Communication between cells ensures coordination of behavior. Research progress of exogenous plant mirnas in crosskingdom. Micrornas mirnas are small, noncoding rnas that regulate gene expression at the posttranscriptional level and play an important role in development, homeostasis, and immunological defense function bartel, 2004. Exogenous plant mir168a specifically targets mammalian. The novel and important functions of the secreted mirnas were also reported by many other groups 1821.
Birth and expression evolution of mammalian microrna genes. May 17, 2011 micrornaprotein complexes micrornps can activate translation of target reporters and specific mrnas in quiescent i. Viral micrornas play an important role in the regulation of gene expression of viral andor host genes to benefit the virus. Understanding how such information is differentially and dynamically retrieved to define distinct cell types and cellular states is a major challenge facing molecular biology. A study was undertaken to determine if mirnas are differentially. Hence, mirnas play a key role in hostvirus interactions and pathogenesis of viral diseases. Background the mechanisms underlying chronic obstructive pulmonary disease copd remain unclear. Regulation of mammalian gene expression by exogenous micrornas hongwei liang, lei huang, jingjing cao, ke zen, xi chen. For more than 20 years, micrornas have been known to act in the cytoplasm to degrade transcriptional expression of specific target gene messenger rnas see microrna history. Since then, hundreds of micrornas have been identified. Characterization, modelling and mitigation of gene. About 37% of mammalian micrornas appear to be located within introns of protein coding genes, linking their expression to the promoterdriven regulation of the host gene. Research progress of exogenous plant mirnas in cross. We report micrornamediated upregulated expression of reporters in immature.
Crosskingdom gene regulation by micrornas mirnas initiated a hot debate on the effective role of orally acquired plant mirnas on human gene expression. In this work, we used a guanineresponsive aptazyme to control transgene expression from a replicationincompetent vesicular stomatitis virus vsv vector. In cancers, loss of expression of genes occurs about 10 times more frequently by transcription silencing caused by promoter hypermethylation of cpg islands than by mutations. Most mirnas are transcribed by the rna polymerase ii and are encoded by introns. Microrna regulation and interspecific variation of gene. Noteworthy, exogenous mirnas have been experimentally proven to regulate gene expression in mammalian cells 37, 39. This hypothesis, in which the crosskingdom regulation is mediated by exogenous plant mirnas. Preferential regulation of duplicated genes by micrornas in. The two founding members of the microrna family were originally identified in caenorhabditis elegans as genes that were required for the timed regulation of developmental events. Howard, a juan cui b a department of nutrition and health sciences, university of nebraskalincoln, 316c leverton hall, lincoln, ne 685830806, usa b department of computer science and engineering, university of nebraskalincoln.
Regulation of gene expression in the mammalian genome, during development, differentiation, and disease, is a complex and multitasked system. Mature micrornas are incorporated into the rnainduced silencing complex and recognize partially complementary. Wrangling for micrornas provokes much crosstalk genome. A number of human diseases including cancer are associated with changes in. Of the three main classes of small regulatory rnas. Exogenous micrornas activate expression of target mrna reporters in the immature oocyte. The transcripts derived from the sv40 simian virus 40 promoter were found to.
Micrornas mirnas modulate expression of their target genes in various tissues and at different developmental stages, but it is unclear whether they drive crossspecies variation in gene expression. Human genes are in silico potential targets for rice mirna. Gene regulation by dietary micrornas canadian journal of. Furthermore, various simirna constructs are widely.
Exogenous plant micrornas in mammalian cells could regulate target gene expression by partial sequence complementarity and translational repression as well as by mrna cleavage. These findings demonstrate that exogenous plant mirnas in food can regulate the expression of target genes in mammals. Regulation of mammalian gene expression by exogenous micrornas. We employed a set of matched constructs, with repeats of a let7 target site in their 3 utr 19, that are identical apart from the promoter used for transcribing the target mrna. Gene regulation by transcription factors and micrornas. In addition to these classical metabolic genes, recent studies in mammalian model systems have shown that micrornas mirnas.
Exogenous micrornas in maternal food pass through placenta. Posttranscriptional activation of gene expression in xenopus. Regulation of mammalian gene expression by exogenous. Generally, this discovery of socalled crosskingdom regulation of gene expression indicates a potentially therapeutic role for plant mirnas, which may be of value in medicine. Plant micrornas in crosskingdom regulation of gene expression. Research article ontogenetic expression of metabolic. Rnabased switches that modulate gene expression are useful to many gene therapy applications because they are small and do not require expression of additional proteins. Transcriptional coregulation of micrornas and protein. Regulated cell metabolism involves acute and chronic regulation of gene expression by various nutritional and endocrine stimuli. Like other classes of rnas in a cell, the biogenesis of micrornas is under the control of various internal and.
Induced quiescent cells, like folliculated immature oocytes, have high levels of camp that activate protein kinase aii pkaii to maintain g0 and immature states. We show here that in moss physcomitrella patens mutants without a dicerlike1b gene, maturation of mirnas. Exogenous plant mir168a specifically targets mammalian ldlrap1. Pdf gene regulation by dietary micrornas researchgate. Micrornas mirnas or mirs are small noncoding rna molecules that modulate the levels of specific genes and proteins. To examine whether this observation is valid in other mammalian species, we analyzed the relationship of mirna target distribution with crossspecies gene expression variation between human and mouse using a gene expression microarray dataset reported by su et alwe calculated the average ev between human and mouse for each gene in 26 different tissues. Like another class of small rnas, sirnas, they affect gene expression posttranscriptionally.
In prokaryotes, this signaling is usually referred to as quorum sensing, while eukaryotic cells communicate through hormones. Posttranscriptional activation of gene expression in. We then refined the model to assess whether the presence of sites of individual mirnas could explain upregulation of targets in an experiment, considering all human mirna families as potential. We tested micrornamediated expression in the g0like immature x. The thesis relates to gene expression regulation within humans and closely related primate species.
Interestingly, mir168a decreased the expression of ldlrap1 protein in mouse liver cells without affecting the encoding mrna levels. Transcriptional coregulation of micrornas and proteincoding. Thousands of mirnas regulating approximately 60 % of the total human genome have been identified. Thousands of micrornas 2123nt ssrnas have been identified in animals over the past seven years 1, 2. These observations implicate small rnas as important mediators of gene regulation in response to cellcell signaling. Subsequent research on mirnas has focused on their biochemical processing and mechanism of action, the scope of their regulatory programs and their differential expression profiles in development and disease. Regulation of mammalian gene expression by exogenous micrornas hongwei liang jiangsu engineering research center for microrna biology and biotechnology, state key laboratory of pharmaceutical biotechnology, school of life sciences, nanjing university, nanjing, china. We injected dna constructs with a cmv promoter and bovine growth hormone polyadenylation sequence or in vitrotranscribed. Here, we describe a novel class of rna switches that conditionally regulate gene expression in mammalian cells through occlusion of a mirt figures 1 and 2d. Micrornas mirnas are small noncoding rnas that regulate expression of various target genes. Department of science and technology, ministry of science and technology npdf. Epigenetic alterations such as dna methylation and histone modification are essential for chromatin remodeling and regulation of gene expression including mirnas. Animals and plants have hundreds of distinct microrna genes, whose regulatory roles in development have been implicated by their diverse expression patterns and, in some cases, confirmed by genetic studies in model organisms and in humans kloosterman and plasterk, 2006.
They are first transcribed as much longer primary transcripts, which then undergo a series of processing steps to yield the singlestranded, mature micrornas. The mammalian intestinal tract is a unique site in which a large portion of our immune system and the 1014 commensal organisms that make up the microbiota reside in intimate contact with each other. The expression of transcription activators by human herpesvirus6 dna is believed to be regulated by viral mirna. Repression of erbb2 in skbr3 breast cancer cells inhibited cellcycle progression by inducing a g1 accumulation, suggesting the potential of designed transcription factors for cancer gene therapy. To respond effectively to endogenous and exogenous signals, cells require rapid response mechanisms to modulate transcript expression and protein synthesis and cannot, in most cases, rely on control of transcriptional. Dietary micrornaa novel functional component of food. A simplified system for the effective expression and delivery of. Thus, secreted mirnas can serve as a novel class of signaling molecules in mediating intercellular communication 15. We have investigated the binding site distributions from publically available chipseq data of 117 transcription regulatory factors trfs within the human genome.
Not surprisingly, given their diverse roles in development, homeobox genes are involved in the regulation of this transition between the resting and activated, or angiogenic, phenotype in ecs. Bioinformatic approaches 1 further suggested that the mammalian mirna repertoire might collectively regulate several thousand genes, even though only a handful of these predicted targets have been validated to date. Regulation of mammalian gene expression by exogenous micrornas hongwei liang jiangsu engineering research center for microrna biology and biotechnology, state key laboratory of pharmaceutical biotechnology, school of. Figure 3b is a cartoon version of the expected effect on expression of a gene that contains different combinations of exogenous and endogenous sites.
Transcriptional coregulation of micrornas and proteincoding genes. Although recent advances have been made in identifying and analyzing instances of micrornamediated gene regulation, it remains unclear by what mechanisms attenuation of transcript expression through micrornas becomes an integral part of posttranscriptional modification, and it is even less clear to what extent this process occurs for mammalian gene. Micrornas mirnas, which are small noncoding rnas expressed by almost all metazoans, have key roles in the regulation of cell differentiation, organism development and gene expression. Micrornamediated control of gene expression via translational inhibition has substantial impact on cellular regulatory mechanisms.
In contrast, in colon tumors compared to adjacent normal. Role of plant microrna in crossspecies regulatory networks of. Gene regulatory factors that control the expression of genomic information come in a variety of flavors, with transcription. These switches use smallmoleculeinduced stem formation to occlude a micrornatarget sequence, thereby activating gene expression. Transcriptional control of gene expression by micrornas. Micrornas are widely expressed, approximately 22nucleotidelong nonproteincoding rnas. Despite the potential for inflammatory immune responses, this complex interface contains host immune cells and epithelial cells interacting with the microbiota in a manner that. Micrornas and the regulation of biological function 1225 kinase promoter 11. Micrornas are short, noncoding rna molecules that can regulate gene expression at the posttranscriptional level. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Transfection of small rnas globally perturbs gene regulation. Characterization, modelling and mitigation of gene expression. In our study we investigate this linkage towards a.
Hongwei liang, lei huang, jingjing cao, ke zen, xi chen. Micrornas mirnas or mirs are small noncoding rnas of 22 nucleotides nt in length, which induce gene silencing by guiding argonaut. They regulate genetic expression either by direct cleavage or by. Regulation of endogenous human gene expression by ligand. Original article exogenous plant mir168a specifically targets mammalian ldlrap1. Regulation of angiogenesis through a microrna mira. They regulate genetic expression either by direct cleavage or by translational repression of the target. We assessed a number of designs using this basic idea and identified switches that provided up to 19fold regulation of gene expression in hela cells. They are thought to act as key regulators of diverse biological and developmental. In our study we investigate this linkage towards a relationship beyond transcriptional co. To make transcripts instead of proteins is energetically less expensive for cells and could be the reason why regulation at the rna level is cheaper and more efficient than at the protein level. To respond effectively to endogenous and exogenous signals, cells require rapid response mechanisms to modulate transcript expression and protein synthesis and cannot, in most cases, rely on control of transcriptional initiation that requires hours to.
The two founding members of the microrna family were originally identified in. We show here that in moss physcomitrella patens mutants without a dicerlike1b gene. While sirnas in addition act in transcriptional gene silencing, a role of mirnas in transcriptional regulation has been less clear. Identification and characterization of hemocyte micrornas. These mirnas are transferred via food intake, and it is likely that the same. These proof of concept experiments demonstrate that. Sep 20, 2011 endogenous mammalian mirnas have a dynamic range of expression, extending from 10 000 copies per cell, and the regulation of target genes is highly dependent on mirna. Synthetic riboswitches based on small moleculeresponsive selfcleaving ribozymes aptazymes embedded in the untranslated regions utrs allow chemical control of gene expression in mammalian cells.
Gene regulation by dietary micrornas article pdf available in canadian journal of physiology and pharmacology 9312. Mar 28, 2008 the properties of a cell are determined by the genetic information encoded in its genome. The regulation of genes and genomes by small rnas development. Despite the potential for inflammatory immune responses, this complex interface contains host immune cells and epithelial cells interacting with the microbiota in a manner that promotes symbiosis. These mirnas are transferred via food intake, and it. Endogenous mammalian mirnas have a dynamic range of expression, extending from 10 000 copies per cell, and the regulation of target genes is highly dependent on mirna. For example, they are essential for the regulation of tissue differentiation during development stefani and slack 2008 and the regulation of the immune response xiao and rajewsky 2009. Frontiers micrornas and the regulation of intestinal. Like other classes of rnas in a cell, the biogenesis of micrornas is under the control of various internal and external cues. Mature mirnas, which are between 18 and 25 bp in length, are transcribed as primarymirna. By comparing data from mammal and fly species we found that the crossspecies expression variation of mirna targets is significantly lower than.
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