Gene autoregulation via intronic microRNAs and its functions

Background: MicroRNAs, post-transcriptional repressors of gene expression, play a pivotal role in gene regulatory networks. They are involved in core cellular processes and their dysregulation is associated to a broad range of human diseases. This paper focus on a minimal microRNA-mediated regulatory circuit, in which a protein-coding gene (host gene) is targeted by a microRNA located inside one of its introns. Results: Autoregulation via intronic microRNAs is widespread in the human regulatory network, as confirmed by our bioinformatic analysis, and can perform several regulatory tasks despite its simple topology. Our analysis, based on analytical calculations and simulations, indicates that this circuitry alters the dynamics of the host gene expression, can induce complex responses implementing adaptation and Weber's law, and efficiently filters fluctuations propagating from the upstream network to the host gene. A fine-tuning of the circuit parameters can optimize each of these functions. Interestingly, they are all related to gene expression homeostasis, in agreement with the increasing evidence suggesting a role of microRNA regulation in conferring robustness to biological processes. In addition to model analysis, we present a list of bioinformatically predicted candidate circuits in human for future experimental tests. Conclusions: The results presented here suggest a potentially relevant functional role for negative self-regulation via intronic microRNAs, in particular as a homeostatic control mechanism of gene expression. Moreover, the map of circuit functions in terms of experimentally measurable parameters, resulting from our analysis, can be a useful guideline for possible applications in synthetic biology.Comment: 29 pages and 7 figures in the main text, 18 pages of Supporting Informatio

MicroRNA Gene Networks in Oncogenesis

MicroRNAs are small non-coding RNAs that regulate gene expression at the transcriptional or posttranscriptional level. They are involved in cellular development, differentiation, proliferation and apoptosis and play a significant role in cancer. Examination of tumor-specific microRNA expression profiles has revealed widespread deregulation of these molecules in diverse cancers. Several studies have shown that microRNAs function either as tumor suppressor genes or oncogenes, whose loss or overexpression respectively has diagnostic and prognostic significance. It seems that microRNAs act as major regulators of gene expression. In this review, we discuss microRNAs’ role in cancer and how microRNAs exert their functions through regulation of their gene targets. Bioinformatic analysis of putative miRNA binding sites has indicated several novel potential gene targets involved in apoptosis, angiogenesis and metastatic mechanisms. Matching computational prediction analysis together with microarray data seems the best method for microRNA gene target identification. MicroRNAs together with transcription factors generate a complex combinatorial code regulating gene expression. Thus, manipulation of microRNA-transcription factor gene networks may be provides a novel approach for developing cancer therapies

Interplay between cardiac transcription factors and non-coding RNAs in predisposing to atrial fibrillation

Review[Abstract] There is growing evidence that putative gene regulatory networks including cardio-enriched transcription factors, such as PITX2, TBX5, ZFHX3, and SHOX2, and their effector/target genes along with downstream non-coding RNAs can play a potentially important role in the process of adaptive and maladaptive atrial rhythm remodeling. In turn, expression of atrial fibrillation-associated transcription factors is under the control of upstream regulatory non-coding RNAs. This review broadly explores gene regulatory mechanisms associated with susceptibility to atrial fibrillation—with key examples from both animal models and patients—within the context of both cardiac transcription factors and non-coding RNAs. These two systems appear to have multiple levels of cross-regulation and act coordinately to achieve effective control of atrial rhythm effector gene expression. Perturbations of a dynamic expression balance between transcription factors and corresponding non-coding RNAs can provoke the development or promote the progression of atrial fibrillation. We also outline deficiencies in current models and discuss ongoing studies to clarify remaining mechanistic questions. An understanding of the function of transcription factors and non-coding RNAs in gene regulatory networks associated with atrial fibrillation risk will enable the development of innovative therapeutic strategies.Galicia. Consellería de Cultura, Educación e Ordenación Universitaria; GRC 2013/06

CircuitsDB: a database of mixed microRNA/transcription factor feed-forward regulatory circuits in human and mouse

<p>Abstract</p> <p>Background</p> <p>Transcription Factors (TFs) and microRNAs (miRNAs) are key players for gene expression regulation in higher eukaryotes. In the last years, a large amount of bioinformatic studies were devoted to the elucidation of transcriptional and post-transcriptional (mostly miRNA-mediated) regulatory interactions, but little is known about the interplay between them.</p> <p>Description</p> <p>Here we describe a dynamic web-accessible database, <monospace>CircuitsDB</monospace>, supporting a genome-wide transcriptional and post-transcriptional regulatory network integration, for the human and mouse genomes, based on a bioinformatic sequence-analysis approach. In particular, <monospace>CircuitsDB</monospace> is currently focused on the study of mixed miRNA/TF Feed-Forward regulatory Loops (FFLs), i.e. elementary circuits in which a master TF regulates an miRNA and together with it a set of Joint Target protein-coding genes. The database was constructed using an ab-initio oligo analysis procedure for the identification of the transcriptional and post-transcriptional interactions. Several external sources of information were then pooled together to obtain the functional annotation of the proposed interactions. Results for human and mouse genomes are presented in an integrated web tool, that allows users to explore the circuits, investigate their sequence and functional properties and thus suggest possible biological experiments.</p> <p>Conclusions</p> <p>We present <monospace>CircuitsDB</monospace>, a web-server devoted to the study of human and mouse mixed miRNA/TF Feed-Forward regulatory circuits, freely available at: <url>http://biocluster.di.unito.it/circuits/</url></p

From Endogenous to Synthetic microRNA-Mediated Regulatory Circuits: An Overview

MicroRNAs are short non-coding RNAs that are evolutionarily conserved and are pivotal post-transcriptional mediators of gene regulation. Together with transcription factors and epigenetic regulators, they form a highly interconnected network whose building blocks can be classified depending on the number of molecular species involved and the type of interactions amongst them. Depending on their topology, these molecular circuits may carry out specific functions that years of studies have related to the processing of gene expression noise. In this review, we first present the different over-represented network motifs involving microRNAs and their specific role in implementing relevant biological functions, reviewing both theoretical and experimental studies. We then illustrate the recent advances in synthetic biology, such as the construction of artificially synthesised circuits, which provide a controlled tool to test experimentally the possible microRNA regulatory tasks and constitute a starting point for clinical applications

Kinetic modelling of competition and depletion of shared miRNAs by competing endogenous RNAs

Non-conding RNAs play a key role in the post-transcriptional regulation of mRNA translation and turnover in eukaryotes. miRNAs, in particular, interact with their target RNAs through protein-mediated, sequence-specific binding, giving rise to extended and highly heterogeneous miRNA-RNA interaction networks. Within such networks, competition to bind miRNAs can generate an effective positive coupling between their targets. Competing endogenous RNAs (ceRNAs) can in turn regulate each other through miRNA-mediated crosstalk. Albeit potentially weak, ceRNA interactions can occur both dynamically, affecting e.g. the regulatory clock, and at stationarity, in which case ceRNA networks as a whole can be implicated in the composition of the cell's proteome. Many features of ceRNA interactions, including the conditions under which they become significant, can be unraveled by mathematical and in silico models. We review the understanding of the ceRNA effect obtained within such frameworks, focusing on the methods employed to quantify it, its role in the processing of gene expression noise, and how network topology can determine its reach.Comment: review article, 29 pages, 7 figure

MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer

We hypothesize that dosage compensation of critical genes arises from systems- level properties for cancer cells to withstand the negative effects of aneuploidy. We identified several candidate genes in cancer multiomics data and developed a biocomputational platform to construct a mathematical model of their interac- tion network with micro-RNAs and transcription factors, where the property of dosage compensation emerged for MYC and was dependent on the kinetic pa- rameters of its feedback interactions with three micro-RNAs. These circuits were experimentally validated using a genetic tug-of-war technique to overex- press an exogenous MYC, leading to overexpression of the three microRNAs involved and downregulation of endogenous MYC. In addition, MYC overexpres- sion or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity in MYC-amplified colon cancer cells. Finally, we identified negative correlation of MYC dosage compensation with patient survival in TCGA breast cancer patients, highlighting the potential of this mechanism to prevent aneu- ploid cancer progression.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Enfermedades Tropicales (CIET)UCR::Vicerrectoría de Investigación::Sistema de Estudios de Posgrado::Salud::Maestría Académica en Bioinformática y Biología de SistemasUCR::Vicerrectoría de Docencia::Ingeniería::Facultad de Ingeniería::Escuela de Ciencias de la Computación e InformáticaUCR::Vicerrectoría de Docencia::Ingeniería::Facultad de Ingeniería::Escuela de Ingeniería EléctricaUCR::Vicerrectoría de Docenci

MicroRNAs in Human Diseases: From Autoimmune Diseases to Skin, Psychiatric and Neurodegenerative Diseases

MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression via degradation or translational repression of their target messenger RNAs (mRNAs). Recent studies have clearly demonstrated that miRNAs play critical roles in several biologic processes, including cell cycle, differentiation, cell development, cell growth, and apoptosis and that miRNAs are highly expressed in regulatory T (Treg) cells and a wide range of miRNAs are involved in the regulation of immunity and in the prevention of autoimmunity. It has been increasingly reported that miRNAs are associated with various human diseases like autoimmune disease, skin disease, neurological disease and psychiatric disease. Recently, the identification of mi- RNAs in skin has added a new dimension in the regulatory network and attracted significant interest in this novel layer of gene regulation. Although miRNA research in the field of dermatology is still relatively new, miRNAs have been the subject of much dermatological interest in skin morphogenesis and in regulating angiogenesis. In addition, miRNAs are moving rapidly onto center stage as key regulators of neuronal development and function in addition to important contributions to neurodegenerative disorder. Moreover, there is now compelling evidence that dysregulation of miRNA networks is implicated in the development and onset of human neruodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Tourette's syndrome, Down syndrome, depression and schizophrenia. In this review, I briefly summarize the current studies about the roles of miRNAs in various autoimmune diseases, skin diseases, psychoneurological disorders and mental stress

MicroRNA Control of TGF-β Signaling

Transcriptional and post-transcriptional regulation shapes the transcriptome and proteome changes induced by various cellular signaling cascades. MicroRNAs (miRNAs) are small regulatory RNAs that are approximately 22 nucleotides long, which direct the post-transcriptional regulation of diverse target genes and control cell states. Transforming growth factor (TGF)-β; family is a multifunctional cytokine family, which plays many regulatory roles in the development and pathogenesis of diverse diseases, including fibrotic disease, cardiovascular disease and cancer. Previous studies have shown that the TGF-β; pathway includes the miRNA pathway as an important component of its downstream signaling cascades. Multiple studies of epithelial&ndash;mesenchymal transition (EMT)-related miRNAs have highlighted that miRNAs constitute the intrinsic bistable molecular switches of cell states by forming double negative feedback loops with EMT-inducing transcription factors. This may be important for understanding the reversibility of EMT at the single-cell level, the presence of distinct EMT transition states and the intra- and inter-tumor heterogeneity of cancer cell phenotypes. In the present review, I summarize the connection between TGF-β; signaling and the miRNA pathway, placing particular emphasis on the regulation of miRNA expression by TGF-β; signaling, the modulation of TGF-β; signaling by miRNAs, the miRNA-mediated modulation of EMT and endothelial&ndash;mesenchymal transition as well as the crosstalk between miRNA and TGF-β; pathways in the tumor microenvironment