Quantitative analysis of competition in post-transcriptional regulation reveals a novel signature in target expression variation

When small RNAs are loaded onto Argonaute proteins they can form the RNA-induced silencing complexes (RISCs), which mediate RNA interference. RISC-formation is dependent on a shared pool of Argonaute proteins and RISC loading factors, and is thus susceptible to competition among small RNAs for loading. We present a mathematical model that aims to understand how small RNA competition for the PTR resources affects target gene repression. We discuss that small RNA activity is limited by RISC-formation, RISC-degradation and the availability of Argonautes. Together, these observations explain a number of PTR saturation effects encountered experimentally. We show that different competition conditions for RISC-loading result in different signatures of PTR activity determined also by the amount of RISC-recycling taking place. In particular, we find that the small RNAs less efficient at RISC-formation, using fewer resources of the PTR pathway, can perform in the low RISC-recycling range equally well as their more effective counterparts. Additionally, we predict a novel signature of PTR in target expression levels. Under conditions of low RISC-loading efficiency and high RISC-recycling, the variation in target levels increases linearly with the target transcription rate. Furthermore, we show that RISC-recycling determines the effect that Argonaute scarcity conditions have on target expression variation. Our observations taken together offer a framework of predictions which can be used in order to infer from experimental data the particular characteristics of underlying PTR activity.Comment: 23 pages, 3 Figures, accepted for publication to the Biophysical Journa

Can we always sweep the details of RNA-processing under the carpet?

RNA molecules follow a succession of enzyme-mediated processing steps from transcription until maturation. The participating enzymes, for example the spliceosome for mRNAs and Drosha and Dicer for microRNAs, are also produced in the cell and their copy-numbers fluctuate over time. Enzyme copy-number changes affect the processing rate of the substrate molecules; high enzyme numbers increase the processing probability, low enzyme numbers decrease it. We study different RNA processing cascades where enzyme copy-numbers are either fixed or fluctuate. We find that for fixed enzyme-copy numbers the substrates at steady-state are Poisson-distributed, and the whole RNA cascade dynamics can be understood as a single birth-death process of the mature RNA product. In this case, solely fluctuations in the timing of RNA processing lead to variation in the number of RNA molecules. However, we show analytically and numerically that when enzyme copy-numbers fluctuate, the strength of RNA fluctuations increases linearly with the RNA transcription rate. This linear effect becomes stronger as the speed of enzyme dynamics decreases relative to the speed of RNA dynamics. Interestingly, we find that under certain conditions, the RNA cascade can reduce the strength of fluctuations in the expression level of the mature RNA product. Finally, by investigating the effects of processing polymorphisms we show that it is possible for the effects of transcriptional polymorphisms to be enhanced, reduced, or even reversed. Our results provide a framework to understand the dynamics of RNA processing

Epigenetic dynamics of monocyte-to-macrophage differentiation

Background Monocyte-to-macrophage differentiation involves major biochemical and structural changes. In order to elucidate the role of gene regulatory changes during this process, we used high-throughput sequencing to analyze the complete transcriptome and epigenome of human monocytes that were differentiated in vitro by addition of colony-stimulating factor 1 in serum-free medium. Results Numerous mRNAs and miRNAs were significantly up- or down-regulated. More than 100 discrete DNA regions, most often far away from transcription start sites, were rapidly demethylated by the ten eleven translocation enzymes, became nucleosome-free and gained histone marks indicative of active enhancers. These regions were unique for macrophages and associated with genes involved in the regulation of the actin cytoskeleton, phagocytosis and innate immune response. Conclusions In summary, we have discovered a phagocytic gene network that is repressed by DNA methylation in monocytes and rapidly de-repressed after the onset of macrophage differentiation

Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN

Circular RNAs (circRNAs) are a regulatory RNA class. While cancer-driving functions have been identified for single circRNAs, how they modulate gene expression in cancer is not well understood. We investigate circRNA expression in the pediatric malignancy, neuroblastoma, through deep whole-transcriptome sequencing in 104 primary neuroblastomas covering all risk groups. We demonstrate that MYCN amplification, which defines a subset of high-risk cases, causes globally suppressed circRNA biogenesis directly dependent on the DHX9 RNA helicase. We detect similar mechanisms in shaping circRNA expression in the pediatric cancer medulloblastoma implying a general MYCN effect. Comparisons to other cancers identify 25 circRNAs that are specifically upregulated in neuroblastoma, including circARID1A. Transcribed from the ARID1A tumor suppressor gene, circARID1A promotes cell growth and survival, mediated by direct interaction with the KHSRP RNA-binding protein. Our study highlights the importance of MYCN regulating circRNAs in cancer and identifies molecular mechanisms, which explain their contribution to neuroblastoma pathogenesis

Phonon-mediated tuning of instabilities in the Hubbard model at half-filling

We obtain the phase diagram of the half-filled two-dimensional Hubbard model on a square lattice in the presence of Einstein phonons. We find that the interplay between the instantaneous electron-electron repulsion and electron-phonon interaction leads to new phases. In particular, a dx2−y2-wave superconducting phase emerges when both anisotropic phonons and repulsive Hubbard interaction are present. For large electron-phonon couplings, charge-density-wave and s-wave superconducting regions also appear in the phase diagram, and the widths of these regions are strongly dependent on the phonon frequency, indicating that retardation effects play an important role. Since at half filling the Fermi surface is nested, a spin-density wave is recovered when the repulsive interaction dominates. We employ a functional multiscale renormalization-group method [Tsai et al., Phys. Rev. B 72, 054531 (2005)] that includes both electron-electron and electron-phonon interactions, and take retardation effects fully into account

Tunneling between two-dimensional electron systems in a high magnetic field: Role of interlayer interactions

We calculate the tunneling current for a bilayer quantum Hall system in the interlayer incoherent regime. In order to capture the strong correlation effects we model the layers as two Wigner crystals coupled through interlayer Coulomb interactions, treated in the continuum limit. By generalizing previous work by Johansson and Kinaret (JK), we are able to study the effect of the low energy out-of-phase magnetophonon modes on the electron "shake-up" which occurs during a tunneling event. We find the tunneling current peak value to scale with the magnetic field as found by JK; however, we find a different scaling of the peak value with the interlayer separation, which agrees with the measurements by Eisenstein et al. [Phys. Rev. Lett. 74, 1419 (1995)]

How epigenetic mutations can affect genetic evolution: Model and mechanism

We hypothesize that heritable epigenetic changes can affect rates of fitness increase as well as patterns of genotypic and phenotypic change during adaptation. In particular, we suggest that when natural selection acts on pure epigenetic variation in addition to genetic variation, populations adapt faster, and adaptive phenotypes can arise before any genetic changes. This may make it difficult to reconcile the timing of adaptive events detected using conventional population genetics tools based on DNA sequence data with environmental drivers of adaptation, such as changes in climate. Epigenetic modifications are frequently associated with somatic cell differentiation, but recently epigenetic changes have been found that can be transmitted over many generations. Here, we show how the interplay of these heritable epigenetic changes with genetic changes can affect adaptive evolution, and how epigenetic changes affect the signature of selection in the genetic record

Characterization of transcription termination associated-RNAs (TTSa-RNAs): new insights into their biogenesis, tailing and expression in primary tumors

Next-generation sequencing has uncovered novel classes of small RNAs(sRNAs)in eukaryotes,in 30addition to the well-known miRNAs, siRNAs and piRNAs.In particular, sRNAspeciesarise from 31transcription start sites (TSSs) and the transcription termination sites (TTSs) of genes. However, a 32detailed characterization of these new classes of sRNAs is still lacking. 33Here we present a comprehensive study of sRNAs derived from TTSsof expressed genes (TTSa-RNAs) 34in human cell lines and primary tissues.Taking advantage of sRNA-sequencing, we show that TTSa-35RNAs are present in the nuclei of human cells, are loaded onto both AGO1 and AGO2 and their 36biogenesis does not requireDICER andAGO2 endonucleolytic activity. TTSa-RNAsdisplay a strong37bias against a G residue in the first position at 5' end, a knownfeature of AGO-bound sRNAs, and a 38peculiar oligoA tail at 3’ end.AGO-bound TTSa-RNAs derive from genes involved in cell cycle 39progression regulationand DNA integrity checkpoints.Finally, we provide evidence that TTSa-RNAs 40can be detected by sRNA-Seq in primary human tissue and their expression increases in tumor samples 41as compared to non-tumor tissues, suggesting that in the future TTSa-RNAs might be explored as 42biomarker for diagnosis or prognosis of human malignancie