7,118 research outputs found
Features of mammalian microRNA promoters emerge from polymerase II chromatin immunoprecipitation data
Background: MicroRNAs (miRNAs) are short, non-coding RNA regulators of protein coding genes. miRNAs play a very important role in diverse biological processes and various diseases. Many algorithms are able to predict miRNA genes and their targets, but their transcription regulation is still under investigation. It is generally believed that intragenic miRNAs (located in introns or exons of protein coding genes) are co-transcribed with their host genes and most intergenic miRNAs transcribed from their own RNA polymerase II (Pol II) promoter. However, the length of the primary transcripts and promoter organization is currently unknown. Methodology: We performed Pol II chromatin immunoprecipitation (ChIP)-chip using a custom array surrounding regions of known miRNA genes. To identify the true core transcription start sites of the miRNA genes we developed a new tool (CPPP). We showed that miRNA genes can be transcribed from promoters located several kilobases away and that their promoters share the same general features as those of protein coding genes. Finally, we found evidence that as many as 26% of the intragenic miRNAs may be transcribed from their own unique promoters. Conclusion: miRNA promoters have similar features to those of protein coding genes, but miRNA transcript organization is more complex. © 2009 Corcoran et al
A combination of transcriptional and microRNA regulation improves the stability of the relative concentrations of target genes
It is well known that, under suitable conditions, microRNAs are able to fine
tune the relative concentration of their targets to any desired value. We show
that this function is particularly effective when one of the targets is a
Transcription Factor (TF) which regulates the other targets. This combination
defines a new class of feed-forward loops (FFLs) in which the microRNA plays
the role of master regulator. Using both deterministic and stochastic equations
we show that these FFLs are indeed able not only to fine-tune the TF/target
ratio to any desired value as a function of the miRNA concentration but also,
thanks to the peculiar topology of the circuit, to ensures the stability of
this ratio against stochastic fluctuations. These two effects are due to the
interplay between the direct transcriptional regulation and the indirect
TF/Target interaction due to competition of TF and target for miRNA binding
(the so called "sponge effect"). We then perform a genome wide search of these
FFLs in the human regulatory network and show that they are characterizedby a
very peculiar enrichment pattern. In particular they are strongly enriched in
all the situations in which the TF and its target have to be precisely kept at
the same concentration notwithstanding the environmental noise. As an example
we discuss the FFL involving E2F1 as Transcription Factor, RB1 as target and
miR-17 family as master regulator. These FFLs ensure a tight control of the
E2F/RB ratio which in turns ensures the stability of the transition from the
G0/G1 to the S phase in quiescent cells.Comment: 23 pages, 10 figure
Molecular medicine of microRNAs: structure, function and implications for diabetes
MicroRNAs (miRNAs) are a family of endogenous small noncoding RNA molecules, of 19–28 nucleotides in length. In humans, up to 3% of all genes are estimated to encode these evolutionarily conserved sequences. miRNAs are thought to control expression of thousands of target mRNAs. Mammalian miRNAs generally negatively regulate gene expression by repressing translation, possibly through effects on mRNA stability and compartmentalisation, and/or the translation process itself. An extensive range of in silico and experimental techniques have been applied to our understanding of the occurrence and functional relevance of such sequences, and antisense technologies have been successfully used to control miRNA expression in vitro and in vivo. Interestingly, miRNAs have been identified in both normal and pathological conditions, including differentiation and development, metabolism, proliferation, cell death, viral infection and cancer. Of specific relevance and excitement to the area of diabetes research, miRNA regulation has been implicated in insulin secretion from pancreatic β-cells, diabetic heart conditions and nephropathy. Further analyses of miRNAs in vitro and in vivo will, undoubtedly, enable us determine their potential to be exploited as therapeutic targets in diabetes
The Nefarious Nexus of Noncoding RNAs in Cancer
The past decade has witnessed enormous progress, which has seen the noncoding RNAs (ncRNAs) turn from the so called dark matter RNA to critical functional molecules, influencing most physiological processes in development and disease contexts. Many ncRNAs interact with each other and are part of networks that influence the cell transcriptome and proteome and consequently the outcome of biological processes. The regulatory circuits controlled by ncRNAs have become increasingly more relevant in cancer. Further understanding of these complex network interactions and how ncRNAs are regulated, is paving the way for the identification of better therapeutic strategies in cancer
MicroRNAs in the stressed heart: Sorting the signal from the noise
The short noncoding RNAs, known as microRNAs, are of undisputed importance in cellular signaling during differentiation and development, and during adaptive and maladaptive responses of adult tissues, including those that comprise the heart. Cardiac microRNAs are regulated by hemodynamic overload resulting from exercise or hypertension, in the response of surviving myocardium to myocardial infarction, and in response to environmental or systemic disruptions to homeostasis, such as those arising from diabetes. A large body of work has explored microRNA responses in both physiological and pathological contexts but there is still much to learn about their integrated actions on individual mRNAs and signaling pathways. This review will highlight key studies of microRNA regulation in cardiac stress and suggest possible approaches for more precise identification of microRNA targets, with a view to exploiting the resulting data for therapeutic purposes
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