Publications by authors named "Julia Makarova"

31 Publications

Low expression of CD24 is associated with poor survival in colorectal cancer.

Biochimie 2021 Oct 9. Epub 2021 Oct 9.

Faculty of Biology and Biotechnology, HSE University, Moscow, Russia; SRC Bioclinicum, Moscow, Russia. Electronic address:

In this study we analyzed expression of CD24 in a cohort of colorectal cancer patients using immunohistochemistry staining of CD24. We found a significant association between absence or low expression of CD24 (10% of membranous and 55% of cytoplasmic staining) and shortened patient survival. Protein localization played a crucial role in the prognosis: membranous form was the major and prognostic one in primary tumors, while cytoplasmic expression was elevated in liver metastases compared to the primary tumors and contained prognostic information. Then, using The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) RNA-seq data, we showed that CD24 mRNA level was two-fold decreased in primary colorectal cancers compared to adjacent normal mucosa. Like the protein staining data, ten percent of patients with the lowest mRNA expression levels of CD24 in primary tumors had reduced survival compared to the ones with higher expression. To explain these findings mechanistically, shRNA-mediated CD24 knockdown was performed in HT-29 colorectal cancer cells. It resulted in the increase of cell migration in vitro, no changes in proliferation and apoptosis, and a slight decrease in cell invasion. As increased cell migration is a hallmark of metastasis formation, this finding corroborates the association of a decreased CD24 expression with poor prognosis. Differential gene expression analysis revealed upregulation of genes involved in cell migration in the group of patients with low CD24 expression, including integrin subunit α3 and α3, β3 subunits of laminin 332. Further co-expression analysis identified SPI1, STAT1 and IRF1 transcription factors as putative master-regulators in this group.
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http://dx.doi.org/10.1016/j.biochi.2021.10.004DOI Listing
October 2021

The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation.

Front Immunol 2021 29;12:661204. Epub 2021 Apr 29.

Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.

Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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http://dx.doi.org/10.3389/fimmu.2021.661204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117219PMC
April 2021

HIF Prolyl Hydroxylase Inhibitors for COVID-19 Treatment: Pros and Cons.

Front Pharmacol 2020 29;11:621054. Epub 2021 Jan 29.

P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia.

The review analyzes the potential advantages and problems associated with using HIF prolyl hydroxylase inhibitors as a treatment for COVID-19. HIF prolyl hydroxylase inhibitors are known to boost endogenous erythropoietin (Epo) and activate erythropoiesis by stabilizing and activating the hypoxia inducible factor (HIF). Recombinant Epo treatment has anti-inflammatory and healing properties, and thus, very likely, will be beneficial for moderate to severe cases of COVID-19. However, HIF PHD inhibition may have a significantly broader effect, in addition to stimulating the endogenous Epo production. The analysis of HIF target genes reveals that some HIF-targets, such as furin, could play a negative role with respect to viral entry. On the other hand, HIF prolyl hydroxylase inhibitors counteract ferroptosis, the process recently implicated in vessel damage during the later stages of COVID-19. Therefore, HIF prolyl hydroxylase inhibitors may serve as a promising treatment of COVID-19 complications, but they are unlikely to aid in the prevention of the initial stages of infection.
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http://dx.doi.org/10.3389/fphar.2020.621054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878396PMC
January 2021

The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways.

Viruses 2020 07 10;12(7). Epub 2020 Jul 10.

Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa.

Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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http://dx.doi.org/10.3390/v12070746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412373PMC
July 2020

Mechanisms of the negative potential associated with Leão's spreading depolarization: A history of brain electrogenesis.

J Cereb Blood Flow Metab 2020 10 24;40(10):1934-1952. Epub 2020 Jun 24.

Department of Translational Neuroscience, Cajal Institute - CSIC, Madrid, Spain.

Spreading depolarization (SD) is a self-propagated wave that provokes transient disorder of numerous cell and tissue functions, and that may kill neurons in metabolically compromised tissue. We examined the mechanisms underlying the main hallmark of SD, a giant extracellular potential (ΔV) for which multiple electromotive forces have been proposed. The end-point is that neurons and not glia, dendritic channels and not spatial currents, and increased sodium conductance rather than potassium gradients, appear to be the main actors in the generation of the negative ΔV. Neuronal currents are established by two mechanisms, a voltage independent dendritic current, and the differential polarization along the neuron membranes. Notably, despite of a marked drop of ion gradients, these evolve significantly during SD, and yet the membrane potential remains clamped at zero no matter how much inward current is present. There may be substantial inward current or none in function of the evolving portion of the neuron dendrites with SD-activated channels. We propose that the ΔV promotes swelling-induced dendritic damage. Understanding SD electrogenesis requires all elements relevant for membrane potential, action currents, field potentials and volume conduction to be jointly considered, and it has already encouraged the search for new targets to limit SD-related pathology.
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http://dx.doi.org/10.1177/0271678X20935998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786845PMC
October 2020

Volume-Conducted Origin of the Field Potential at the Lateral Habenula.

Front Syst Neurosci 2019 8;13:78. Epub 2020 Jan 8.

Grupo de Neurociencia de Sistemas, Instituto de Fisiología y Biofísica "Houssay" (IFIBIO "Houssay"), Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina.

Field potentials (FPs) are easily reached signals that provide information about the brain's processing. However, FP should be interpreted cautiously since their biophysical bases are complex. The lateral habenula (LHb) is a brain structure involved in the encoding of aversive motivational values. Previous work indicates that the activity of the LHb is relevant for hippocampal-dependent learning. Moreover, it has been proposed that the interaction of the LHb with the hippocampal network is evidenced by the synchronization of LHb and hippocampal FPs during theta rhythm. However, the origin of the habenular FP has not been analyzed. Hence, its validity as a measurement of LHb activity has not been proven. In this work, we used electrophysiological recordings in anesthetized rats and feed-forward modeling to investigate biophysical basis of the FP recorded in the LHb. Our results indicate that the FP in the LHb during theta rhythm is a volume-conducted signal from the hippocampus. This result highlight that FPs must be thoroughly analyzed before its biological interpretation and argues against the use of the habenular FP signal as a readout of the activity of the LHb.
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http://dx.doi.org/10.3389/fnsys.2019.00078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961596PMC
January 2020

The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis.

Cells 2019 11 24;8(12). Epub 2019 Nov 24.

Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.

The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.
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http://dx.doi.org/10.3390/cells8121504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953055PMC
November 2019

Slow-Wave Activity in the S1HL Cortex Is Contributed by Different Layer-Specific Field Potential Sources during Development.

J Neurosci 2019 11 23;39(45):8900-8915. Epub 2019 Sep 23.

Departamentos de Neurociencia Traslacional, y

Spontaneous correlated activity in cortical columns is critical for postnatal circuit refinement. We used spatial discrimination techniques to explore the late maturation of synaptic pathways through the laminar distribution of the field potential (FP) generators underlying spontaneous and evoked activities of the S1HL cortex in juvenile (P14-P16) and adult anesthetized rats. Juveniles exhibit an intermittent FP pattern resembling Up/Down states in adults, but with much reduced power and different laminar distribution. Whereas FPs in active periods are dominated by a layer VI generator in juveniles, in adults a developing multipart generator takes over, displaying current sinks in middle layers (III-V). The blockade of excitatory transmission in upper and middle layers of adults recovered the juvenile-like FP profiles. In addition to the layer VI generator, a gamma-specific generator in supragranular layers was the same in both age groups. While searching for dynamical coupling among generators in juveniles we found significant cross-correlation in ∼one-half of the tested pairs, whereas excessive coherence hindered their efficient separation in adults. Also, potentials evoked by tactile and electrical stimuli showed different short-latency dipoles between the two age groups, and the juveniles lacked the characteristic long latency UP state currents in middle layers. In addition, the mean firing rate of neurons was lower in juveniles. Thus, cortical FPs originate from different intra-columnar segments as they become active postnatally. We suggest that although some cortical segments are active early postnatally, a functional sensory-motor control relies on a delayed maturation and network integration of synaptic connections in middle layers. Early postnatal activity in the rodent cortex is mostly endogenous, whereas it becomes driven by peripheral input at later stages. The precise schedule for the maturation of synaptic pathways is largely unknown. We explored this in the somatosensory hindlimb cortex at an age when animals begin to use their limbs by uncovering the laminar distribution of the field potential generators underlying the dominant delta waves in juveniles and adults. Our results suggest that field potentials are mostly generated by a pathway in deep layers, whereas other pathways mature later in middle layers and take over in adults. We suggest that a functional sensory-motor control relies on a delayed maturation and network integration of synaptic connections in middle layers.
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http://dx.doi.org/10.1523/JNEUROSCI.1212-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832678PMC
November 2019

Local and Volume-Conducted Contributions to Cortical Field Potentials.

Cereb Cortex 2019 12;29(12):5234-5254

Department of Translational Neuroscience, Cajal Institute - CSIC, Av. Dr. Arce 37, Madrid, Spain.

Brain field potentials (FPs) can reach far from their sources, making difficult to know which waves come from where. We show that modern algorithms efficiently segregate the local and remote contributions to cortical FPs by recovering the generator-specific spatial voltage profiles. We investigated experimentally and numerically the local and remote origin of FPs in different cortical areas in anesthetized rats. All cortices examined show significant state, layer, and region dependent contribution of remote activity, while the voltage profiles help identify their subcortical or remote cortical origin. Co-activation of different cortical modules can be discriminated by the distinctive spatial features of the corresponding profiles. All frequency bands contain remote activity, thus influencing the FP time course, in cases drastically. The reach of different FP patterns is boosted by spatial coherence and curved geometry of the sources. For instance, slow cortical oscillations reached the entire brain, while hippocampal theta reached only some portions of the cortex. In anterior cortices, most alpha oscillations have a remote origin, while in the visual cortex the remote theta and gamma even surpass the local contribution. The quantitative approach to local and distant FP contributions helps to refine functional connectivity among cortical regions, and their relation to behavior.
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http://dx.doi.org/10.1093/cercor/bhz061DOI Listing
December 2019

High-Dimensional Brain: A Tool for Encoding and Rapid Learning of Memories by Single Neurons.

Bull Math Biol 2019 11 19;81(11):4856-4888. Epub 2018 Mar 19.

Instituto de Matemática Interdisciplinar, Faculty of Mathematics, Universidad Complutense de Madrid, Avda Complutense s/n, 28040, Madrid, Spain.

Codifying memories is one of the fundamental problems of modern Neuroscience. The functional mechanisms behind this phenomenon remain largely unknown. Experimental evidence suggests that some of the memory functions are performed by stratified brain structures such as the hippocampus. In this particular case, single neurons in the CA1 region receive a highly multidimensional input from the CA3 area, which is a hub for information processing. We thus assess the implication of the abundance of neuronal signalling routes converging onto single cells on the information processing. We show that single neurons can selectively detect and learn arbitrary information items, given that they operate in high dimensions. The argument is based on stochastic separation theorems and the concentration of measure phenomena. We demonstrate that a simple enough functional neuronal model is capable of explaining: (i) the extreme selectivity of single neurons to the information content, (ii) simultaneous separation of several uncorrelated stimuli or informational items from a large set, and (iii) dynamic learning of new items by associating them with already "known" ones. These results constitute a basis for organization of complex memories in ensembles of single neurons. Moreover, they show that no a priori assumptions on the structural organization of neuronal ensembles are necessary for explaining basic concepts of static and dynamic memories.
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http://dx.doi.org/10.1007/s11538-018-0415-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874527PMC
November 2019

Comprehensive network of miRNA-induced intergenic interactions and a biological role of its core in cancer.

Sci Rep 2018 02 5;8(1):2418. Epub 2018 Feb 5.

SRC Bioclinicum, Ugreshskaya str. 2/85, 115088, Moscow, Russia.

MicroRNAs (miRNAs) are a family of short noncoding RNAs that posttranscriptionally regulate gene expression and play an important role in multiple cellular processes. A significant percentage of miRNAs are intragenic, which is often functionally related to their host genes playing either antagonistic or synergistic roles. In this study, we constructed and analyzed the entire network of intergenic interactions induced by intragenic miRNAs. We further focused on the core of this network, which was defined as a union of nontrivial strongly connected components, i.e., sets of nodes (genes) mutually connected via directed paths. Both the entire network and its core possessed statistically significant non-random properties. Specifically, genes forming the core had high expression levels and low expression variance. Furthermore, the network core did not split into separate components corresponding to individual signalling or metabolic pathways, but integrated genes involved in key cellular processes, including DNA replication, transcription, protein homeostasis and cell metabolism. We suggest that the network core, consisting of genes mutually regulated by their intragenic miRNAs, could coordinate adjacent pathways or homeostatic control circuits, serving as a horizontal inter-circuit link. Notably, expression patterns of these genes had an efficient prognostic potential for breast and colorectal cancer patients.
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http://dx.doi.org/10.1038/s41598-018-20215-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799291PMC
February 2018

The biological and diagnostic role of miRNA's in hepatocellular carcinoma.

Front Biosci (Landmark Ed) 2018 03 1;23:1701-1720. Epub 2018 Mar 1.

Hertsen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 125284, Moscow, Russian Federation, Russia.

The potential of exploitation of miRNA as diagnostic agents and therapeutic tools will likely only be realized when a complete knowledge of their biology is revealed. Despite more than a decade of research, the use of miRNA as diagnostic and therapeutic tools remains a 'work in progress'. The objective of this review is to explore more recent developments in the role of deregulated miRNAs in hepatocellular carcinoma (HCC). This includes emerging insights involving miRNA biogenesis, their deregulation by cancer and their role in deregulating the principal HCC cancer pathways. Specific attention is directed at the role of deregulated miRNAs in HCC in a developing country context with high hepatitis B/C burden, as well as an examination of the challenges that confront the use of extracellular miRNAs as commercially viable diagnostic tools to detect early stage HCC.
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http://dx.doi.org/10.2741/4668DOI Listing
March 2018

Selectin-independent adhesion during ovarian cancer metastasis.

Biochimie 2017 Nov 14;142:197-206. Epub 2017 Sep 14.

P. Herzen Moscow Oncology Research Institute, Moscow, 125284, Russia. Electronic address:

Purpose: Ovarian cancer (OvCa) progression mainly takes place by intraperitoneal spread. Adhesion of tumor cells to the mesothelial cells which form the inner surface of the peritoneum is a crucial step in this process. Cancer cells use in principle different molecules of the leukocyte adhesion cascade to facilitate adhesion. This cascade is initiated by selectin-ligand interactions followed by integrin - extracellular matrix protein interactions. Here we address the question whether all tumor cells predominantly employ selectin-dependent leukocyte-like adhesion cascade (SDAC) or whether they use integrin mediated adhesion for OvCa progression as well.

Methods: A comparative transcriptomic analysis of the human OvCa cell lines OVCAR8 and SKOV3 was performed. Intraperitoneal xenograft model of OVCAR8 cells was used to determine whether there is a correlation between SDAC gene expression and the metastatic potential of the control cells and the cells overexpressing c-Fos. Transcriptomic analysis of OVCAR8 and SKOV3 samples was performed using microarrays.

Results: One-third of the protein-coding genes involved in SDAC exhibited lower expression levels in OVCAR8 than in SKOV3 cells. In contrast to SKOV3 cells, c-Fos overexpression in OVCAR8 cells did not significantly influence the expression of SDAC genes. Intraperitoneal xenograft model of OVCAR8 cells unexpectedly demonstrated that the aggressiveness of OVCAR8 tumors was not depended on the c-Fos expression level and was comparable to that of SKOV3 control tumors. Gene expression analysis of tumors suggests that SKOV3-derived tumor progression was mainly depended on SDAC. Progression of OVCAR8 tumors relied on other cell adhesion molecules that do not interact with selectins.

Conclusions: High expression of c-Fos in ovarian cancer cells is not always associated with reduced metastatic potential. Low expression level of SDAC genes may not ensure low OvCa metastatic potential hence alternative adhesion mechanisms involving laminin-integrin interactions exist as well.
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http://dx.doi.org/10.1016/j.biochi.2017.09.009DOI Listing
November 2017

The right hippocampus leads the bilateral integration of gamma-parsed lateralized information.

Elife 2016 09 6;5. Epub 2016 Sep 6.

Department of Translational Neuroscience, Cajal Institute - CSIC, Madrid, Spain.

It is unclear whether the two hippocampal lobes convey similar or different activities and how they cooperate. Spatial discrimination of electric fields in anesthetized rats allowed us to compare the pathway-specific field potentials corresponding to the gamma-paced CA3 output (CA1 Schaffer potentials) and CA3 somatic inhibition within and between sides. Bilateral excitatory Schaffer gamma waves are generally larger and lead from the right hemisphere with only moderate covariation of amplitude, and drive CA1 pyramidal units more strongly than unilateral waves. CA3 waves lock to the ipsilateral Schaffer potentials, although bilateral coherence was weak. Notably, Schaffer activity may run laterally, as seen after the disruption of the connecting pathways. Thus, asymmetric operations promote the entrainment of CA3-autonomous gamma oscillators bilaterally, synchronizing lateralized gamma strings to converge optimally on CA1 targets. The findings support the view that interhippocampal connections integrate different aspects of information that flow through the left and right lobes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050016PMC
http://dx.doi.org/10.7554/eLife.16658DOI Listing
September 2016

Intracellular and extracellular microRNA: An update on localization and biological role.

Prog Histochem Cytochem 2016 11 25;51(3-4):33-49. Epub 2016 Jun 25.

Hertsen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 125284, Moscow, Russian Federation. Electronic address:

MicroRNA (miRNA) is a class of small non-coding RNAs which mediate post-transcriptional gene silencing (PTGS) by sequence-specific inhibition of target mRNAs translation and/or lowering their half-lives in the cytoplasm. Together with their binding partners, Argonaute (AGO) proteins, miRNAs form cores of RNA-induced silencing complexes (RISC). Despite a substantial progress in understanding RISC structure, until recently little was known about its localization in the cell. This review is aimed to provide an overview of the emerging picture of miRNA and RISC localization and function both in the intracellular space and outside of the cell. In contrast to the common assumption that PTGS occurs in the cytoplasm, it was found to operate mainly on the membranes of the endoplasmic reticulum (ER). Besides ER membranes miRNAs were found in all main cellular compartments including nucleus, nucleolus and mitochondria where they regulate various processes including transcription, translation, alternative splicing and DNA repair. Moreover, a certain pool of miRNAs may not be associated with RISC and carry completely different functions. Finally, the discovery of cell-free miRNAs in all biological fluids suggests that miRNAs might also act as signaling molecules outside the cell, and may be utilized as biomarkers for a variety of diseases. In this review we discuss miRNA secretion mechanisms and possible pathways of cell-cell communication via miRNA-containing exosomes in vivo.
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http://dx.doi.org/10.1016/j.proghi.2016.06.001DOI Listing
November 2016

PyramidalExplorer: A New Interactive Tool to Explore Morpho-Functional Relations of Human Pyramidal Neurons.

Front Neuroanat 2015 6;9:159. Epub 2016 Jan 6.

Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biomédica, Universidad Politécnica de MadridMadrid, Spain; Instituto Cajal, Consejo Superior de Investigaciones CientíficasMadrid, Spain.

This work presents PyramidalExplorer, a new tool to interactively explore and reveal the detailed organization of the microanatomy of pyramidal neurons with functionally related models. It consists of a set of functionalities that allow possible regional differences in the pyramidal cell architecture to be interactively discovered by combining quantitative morphological information about the structure of the cell with implemented functional models. The key contribution of this tool is the morpho-functional oriented design that allows the user to navigate within the 3D dataset, filter and perform Content-Based Retrieval operations. As a case study, we present a human pyramidal neuron with over 9000 dendritic spines in its apical and basal dendritic trees. Using PyramidalExplorer, we were able to find unexpected differential morphological attributes of dendritic spines in particular compartments of the neuron, revealing new aspects of the morpho-functional organization of the pyramidal neuron.
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http://dx.doi.org/10.3389/fnana.2015.00159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701943PMC
January 2016

Diversity of LFPs Activated in Different Target Regions by a Common CA3 Input.

Cereb Cortex 2016 10 22;26(10):4082-4100. Epub 2015 Sep 22.

Department of Systems Neuroscience, Cajal Institute-CSIC, Madrid 28002, Spain.

Identifying the pathways contributing to local field potential (LFP) events and oscillations is essential to determine whether synchronous interregional patterns indicate functional connectivity. Here, we studied experimentally and numerically how different target structures receiving input from a common population shape their LFPs. We focused on the bilateral CA3 that sends gamma-paced excitatory packages to the bilateral CA1, the lateral septum, and itself (recurrent input). The CA3-specific contribution was isolated from multisite LFPs in target regions using spatial discrimination techniques. We found strong modulation of LFPs by target-specific features, including the morphology and population arrangement of cells, the timing of CA3 inputs, volume conduction from nearby targets, and co-activated inhibition. Jointly they greatly affect the LFP amplitude, profile, and frequency characteristics. For instance, ipsilateral (Schaffer) LFPs occluded contralateral ones, and septal LFPs arise mostly from remote sources while local contribution from CA3 input was minor. In the CA3 itself, gamma waves have dual origin from local networks: in-phase excitatory and nearly antiphase inhibitory. Also, waves may have different duration and varying phase in different targets. These results indicate that to explore the cellular basis of LFPs and the functional connectivity between structures, besides identifying the origin population/s, target modifiers should be considered.
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http://dx.doi.org/10.1093/cercor/bhv211DOI Listing
October 2016

Exercise immunology meets MiRNAs.

Exerc Immunol Rev 2014 ;20:135-64

A large body of evidence indicates modified expression of protein-coding genes in response to different kinds of physical activity. Recent years have exposed another level of regulation of cellular processes mediated by non-coding RNAs. MicroRNAs (miRNAs) are one of the largest families of non-coding RNAs. MiRNAs mediate post-transcriptional regulation of gene expression. The amount of data supporting the key role of miRNAs in the adaptation of the immune and other body systems to exercise steadily grows. MiRNAs change their expression profiles after exercise and seem to be involved in regulation of exercise-responsive genes in immune and other cell types. Here we discuss existing data and future directions in the field.
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July 2014

Can pathway-specific LFPs be obtained in cytoarchitectonically complex structures?

Front Syst Neurosci 2014 1;8:66. Epub 2014 May 1.

Department of Systems Neuroscience, Cajal Institute-CSIC Madrid, Spain.

Deciphering how the brain encodes the continuous flow of information contained in natural stimuli requires understanding the spontaneous activity of functional assemblies in multiple neuronal populations. A promising integrative approach that combines multisite recordings of local field potentials (LFP) with an independent component analysis (ICA) enables continuous readouts of population specific activities of functionally different neuron groups to be obtained. We previously used this technique successfully in the hippocampus, a single-layer neuronal structure. Here we provide numerical evidence that the cytoarchitectonic complexity of other brain structures does not compromise the value of the ICA-separated LFP components, given that spatial sampling of LFP is representative. The spatial distribution of an LFP component may be quite complex due to folded and multilayered structure of the neuronal aggregate. Nevertheless, the time course of each LFP component is still a reliable postsynaptic convolution of spikes fired by a homogeneous afferent population. This claim is supported by preliminary experimental data obtained in the lateral geniculate nucleus of the awake monkey.
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http://dx.doi.org/10.3389/fnsys.2014.00066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013467PMC
May 2014

Determining the true polarity and amplitude of synaptic currents underlying gamma oscillations of local field potentials.

PLoS One 2013 20;8(9):e75499. Epub 2013 Sep 20.

Department of Systems Neuroscience, Cajal Institute - Consejo Superior de Investigaciones Científicas, Madrid, Spain.

Fluctuations in successive waves of oscillatory local field potentials (LFPs) reflect the ongoing processing of neuron populations. However, their amplitude, polarity and synaptic origin are uncertain due to the blending of electric fields produced by multiple converging inputs, and the lack of a baseline in standard AC-coupled recordings. Consequently, the estimation of underlying currents by laminar analysis yields spurious sequences of inward and outward currents. We devised a combined analytical/experimental approach that is suitable to study laminated structures. The approach was essayed on an experimental oscillatory LFP as the Schaffer-CA1 gamma input in anesthetized rats, and it was verified by parallel processing of model LFPs obtained through a realistic CA1 aggregate of compartmental units. This approach requires laminar LFP recordings and the isolation of the oscillatory input from other converging pathways, which was achieved through an independent component analysis. It also allows the spatial and temporal components of pathway-specific LFPs to be separated. While reconstructed Schaffer-specific LFPs still show spurious inward/outward current sequences, these were clearly stratified into distinct subcellular domains. These spatial bands guided the localized delivery of neurotransmitter blockers in experiments. As expected, only Glutamate but not GABA blockers abolished Schaffer LFPs when applied to the active but not passive subcellular domains of pyramidal cells. The known chemical nature of the oscillatory LFP allowed an empirical offset of the temporal component of Schaffer LFPs, such that following reconstruction they yield only sinks or sources at the appropriate sites. In terms of number and polarity, some waves increased and others decreased proportional to the concomitant inputs in native multisynaptic LFPs. Interestingly, the processing also retrieved the initiation time for each wave, which can be used to discriminate afferent from postsynaptic cells in standard spike-phase correlations. The applicability of this approach to other pathways and structures is discussed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075499PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779195PMC
May 2014

Cytoarchitectonic and dynamic origins of giant positive local field potentials in the dentate gyrus.

J Neurosci 2013 Sep;33(39):15518-32

Department of Systems Neuroscience, Cajal Institute, CSIC, Madrid 28002, Spain, Department of Applied Physics III, Faculty of Physics, Universidad Complutense de Madrid, Madrid 28040, Spain, and Department of Applied Mathematics, Faculty of Mathematics, Universidad Complutense de Madrid, Madrid 28040, Spain.

To determine why some pathways but not others produce sizable local field potentials (LFPs) and how far from the source can these be recorded, complementary experimental analyses and realistic modeling of specific brain structures are required. In the present study, we combined multiple in vivo linear recordings in rats and a tridimensional finite element model of the dentate gyrus, a curved structure displaying abnormally large positive LFPs. We demonstrate that the polarized dendritic arbour of granule cells (GCs), combined with the curved layered configuration of the population promote the spatial clustering of GC currents in the interposed hilus and project them through the open side at a distance from cell domains. LFPs grow up to 20 times larger than observed in synaptic sites. The dominant positive polarity of hilar LFPs was only produced by the synchronous activation of GCs in both blades by either somatic inhibition or dendritic excitation. Moreover, the corresponding anatomical pathways must project to both blades of the dentate gyrus as even a mild decrease in the spatial synchronization resulted in a dramatic reduction in LFP power in distant sites, yet not in the GC domains. It is concluded that the activation of layered structures may establish sharply delimited spatial domains where synaptic currents from one or another input appear to be segregated according to the topology of afferent pathways and the cytoarchitectonic features of the target population. These also determine preferred directions for volume conduction in the brain, of relevance for interpretation of surface EEG recordings.
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http://dx.doi.org/10.1523/JNEUROSCI.0338-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618450PMC
September 2013

SNOntology: Myriads of novel snoRNAs or just a mirage?

BMC Genomics 2011 Nov 3;12:543. Epub 2011 Nov 3.

Background: Small nucleolar RNAs (snoRNAs) are a large group of non-coding RNAs (ncRNAs) that mainly guide 2'-O-methylation (C/D RNAs) and pseudouridylation (H/ACA RNAs) of ribosomal RNAs. The pattern of rRNA modifications and the set of snoRNAs that guide these modifications are conserved in vertebrates. Nearly all snoRNA genes in vertebrates are localized in introns of other genes and are processed from pre-mRNAs. Thus, the same promoter is used for the transcription of snoRNAs and host genes.

Results: The series of studies by Dahai Zhu and coworkers on snoRNAs and their genes were critically considered. We present evidence that dozens of species-specific snoRNAs that they described in vertebrates are experimental artifacts resulting from the improper use of Northern hybridization. The snoRNA genes with putative intrinsic promoters that were supposed to be transcribed independently proved to contain numerous substitutions and are, most likely, pseudogenes. In some cases, they are localized within introns of overlooked host genes. Finally, an increased number of snoRNA genes in mammalian genomes described by Zhu and coworkers is also an artifact resulting from two mistakes. First, numerous mammalian snoRNA pseudogenes were considered as genes, whereas most of them are localized outside of host genes and contain substitutions that question their functionality. Second, Zhu and coworkers failed to identify many snoRNA genes in non-mammalian species. As an illustration, we present 1352 C/D snoRNA genes that we have identified and annotated in vertebrates.

Conclusions: Our results demonstrate that conclusions based only on databases with automatically annotated ncRNAs can be erroneous. Special investigations aimed to distinguish true RNA genes from their pseudogenes should be done. Zhu and coworkers, as well as most other groups studying vertebrate snoRNAs, give new names to newly described homologs of human snoRNAs, which significantly complicates comparison between different species. It seems necessary to develop a uniform nomenclature for homologs of human snoRNAs in other vertebrates, e.g., human gene names prefixed with several-letter code denoting the vertebrate species.
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http://dx.doi.org/10.1186/1471-2164-12-543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349704PMC
November 2011

Parallel readout of pathway-specific inputs to laminated brain structures.

Front Syst Neurosci 2011 13;5:77. Epub 2011 Sep 13.

Department of Systems Neuroscience, Consejo Superior de Investigaciones Científicas, Cajal Institute Madrid, Spain.

Local field potentials (LFPs) capture the electrical activity produced by principal cells during integration of converging synaptic inputs from multiple neuronal populations. However, since synaptic currents mix in the extracellular volume, LFPs have complex spatiotemporal structure, making them hard to exploit. Here we propose a biophysical framework to identify and separate LFP-generators. First we use a computational multineuronal model that scales up single cell electrogenesis driven by several synaptic inputs to realistic aggregate LFPs. This approach relies on the fixed but distinct locations of synaptic inputs from different presynaptic populations targeting a laminated brain structure. Thus the LFPs are contributed by several pathway-specific LFP-generators, whose electrical activity is defined by the spatial distribution of synaptic terminals and the time course of synaptic currents initiated in target cells by the corresponding presynaptic population. Then we explore the efficacy of independent component analysis to blindly separate converging sources and reconstruct pathway-specific LFP-generators. This approach can optimally locate synaptic inputs with subcellular accuracy while the reconstructed time course of pathway-specific LFP-generators is reliable in the millisecond scale. We also describe few cases where the non-linear intracellular interaction of strongly overlapping LFP-generators may lead to a significant cross-contamination and the appearance of derivative generators. We show that the approach reliably disentangle ongoing LFPs in the hippocampus into contribution of several LFP-generators. We were able to readout in parallel the pathway-specific presynaptic activity of projection cells in the entorhinal cortex and pyramidal cells in the ipsilateral and contralateral CA3. Thus we provide formal mathematical and experimental support for parallel readout of the activity of converging presynaptic populations in working neuronal circuits from common LFPs.
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http://dx.doi.org/10.3389/fnsys.2011.00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171694PMC
November 2011

Altered postnatal development of cortico-hippocampal neuronal electric activity in mice deficient for the mitochondrial aspartate-glutamate transporter.

J Cereb Blood Flow Metab 2012 Feb 21;32(2):306-17. Epub 2011 Sep 21.

Department of Systems Neuroscience, Cajal Institute-CSIC, Madrid, Spain.

The deficiency in the mitochondrial aspartate/glutamate transporter Aralar/AGC1 results in a loss of the malate-aspartate NADH shuttle in the brain neurons, hypomyelination, and additional defects in the brain metabolism. We studied the development of cortico/hippocampal local field potential (LFP) in Aralar/AGC1 knockout (KO) mice. Laminar profiles of LFP, evoked potentials, and unit activity were recorded under anesthesia in young (P15 to P22) Aralar-KO and control mice as well as control adults. While LFP power increased 3 to 7 times in both cortex and hippocampus of control animals during P15 to P22, the Aralar-KO specimens hardly progressed. The divergence was more pronounced in the CA3/hilus region. In parallel, spontaneous multiunit activity declined severely in KO mice. Postnatal growth of hippocampal-evoked potentials was delayed in KO mice, and indicated abnormal synaptic and spike electrogenesis and reduced output at P20 to P22. The lack of LFP development in KO mice was accompanied by the gradual appearance of epileptic activity in the CA3/hilus region that evolved to status epilepticus. Strikingly, CA3 bursts were poorly conducted to the CA1 field. We conclude that disturbed substrate supply to neuronal mitochondria impairs development of cortico-hippocampal LFPs. Aberrant neuronal electrogenesis and reduced neuron output may explain circuit dysfunction and phenotype deficiencies.
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http://dx.doi.org/10.1038/jcbfm.2011.129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272597PMC
February 2012

Generation of sustained field potentials by gradients of polarization within single neurons: a macroscopic model of spreading depression.

J Neurophysiol 2010 May 10;103(5):2446-57. Epub 2010 Mar 10.

Cajal Institute, Consejo Superior de Investigaciones, Madrid, Spain.

Spreading depression (SD) is a pathological wave of depolarization of the neural tissue producing a negative macroscopic field potential (V(o)), used as a marker for diagnostic purposes. The cellular basis of SD and neuronal mechanisms of generation of V(o) at the microscopic level are poorly understood. Using a CA1 mathematical model and experimental verification, we examined how transmembrane currents in single cells scale up in the extracellular space shaping V(o). The model includes an array of 17,000 realistically modeled neurons (responsible for generating transmembrane currents) dynamically coupled to a virtual aggregate/extracellular space (responsible for V(o)). The SD wave in different tissue bands is simulated by imposing membrane shunts in the corresponding dendritic elements as suggested by experimentally assessed drop in membrane resistance. We show that strong isopotential depolarization of wide domains (as in the main SD phase) produce broad central cancellation of axial and transmembrane currents in single cells. When depolarization is restricted to narrow dendritic domains (as in the late SD phase), the internal cancellation shrinks and the transmembrane current increases. This explains why in the laminated CA1 the V(o) is smaller in the main phase of SD, when both dendritic layers are seized, than in the SD tail restricted to an apical band. Moreover, scattering of the neuronal somatas (as in cortical regions) further decreases the aggregate V(o) due to the volume averaging. Although mechanistically the V(o) associated to SD is similar to customary transient fields, its changes maybe related to spatial factors in single cells rather than cell number or depolarization strength.
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http://dx.doi.org/10.1152/jn.01045.2009DOI Listing
May 2010

Disentanglement of local field potential sources by independent component analysis.

J Comput Neurosci 2010 Dec 23;29(3):445-57. Epub 2010 Jan 23.

Department of Applied Mathematics, Faculty of Mathematics, Av. Complutense s/n, Univ. Complutense, Madrid, 28040, Spain.

The spontaneous activity of working neurons yields synaptic currents that mix up in the volume conductor. This activity is picked up by intracerebral recording electrodes as local field potentials (LFPs), but their separation into original informative sources is an unresolved problem. Assuming that synaptic currents have stationary placing we implemented independent component model for blind source separation of LFPs in the hippocampal CA1 region. After suppressing contaminating sources from adjacent regions we obtained three main local LFP generators. The specificity of the information contained in isolated generators is much higher than in raw potentials as revealed by stronger phase-spike correlation with local putative interneurons. The spatial distribution of the population synaptic input corresponding to each isolated generator was disclosed by current-source density analysis of spatial weights. The found generators match with axonal terminal fields from subtypes of local interneurons and associational fibers from nearby subfields. The found distributions of synaptic currents were employed in a computational model to reconstruct spontaneous LFPs. The phase-spike correlations of simulated units and LFPs show laminar dependency that reflects the nature and magnitude of the synaptic currents in the targeted pyramidal cells. We propose that each isolated generator captures the synaptic activity driven by a different neuron subpopulation. This offers experimentally justified model of local circuits creating extracellular potential, which involves distinct neuron subtypes.
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http://dx.doi.org/10.1007/s10827-009-0206-yDOI Listing
December 2010

Analysis of C/D box snoRNA genes in vertebrates: The number of copies decreases in placental mammals.

Genomics 2009 Jul 9;94(1):11-9. Epub 2009 Mar 9.

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov St., Moscow 119991, Russia.

C/D box small nucleolar RNAs (snoRNAs) guide site-specific 2'-O-methylation of RNAs. Nearly all C/D box snoRNAs with known targets are involved in rRNA modification. In vertebrates, snoRNAs are encoded in introns of various genes and their processing is coupled with splicing of host gene pre-mRNA. Here, the genes encoding C/D box snoRNAs that guide 2'-O-methylation of rRNA were identified and analyzed in vertebrate genomes. The number of copies of most C/D box snoRNA genes proved to be lower in placental mammals compared to other vertebrates. This can be due to smaller oocytes and accordingly lower number of ribosomes in them in eutherians. The targets of snoRNAs encoded by single-copy and multiple-copy genes proved to have different distribution in rRNAs. The causes of this difference are discussed. In some cases, the transcripts of homologous C/D box RNA genes were shown to guide the modification of neighboring nucleotides in rRNA. C/D box snoRNA pseudogenes were found in all vertebrate classes. Three novel C/D box snoRNAs were found in Xenopus tropicalis that may guide 2'-O-methylation of Xenopus-specific rRNA sites. A list of 922 annotated C/D box snoRNA genes is presented.
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http://dx.doi.org/10.1016/j.ygeno.2009.02.003DOI Listing
July 2009

Variations in tissue resistivity and in the extension of activated neuron domains shape the voltage signal during spreading depression in the CA1 in vivo.

Eur J Neurosci 2008 Jan;27(2):444-56

Cajal Institute, CSIC, Av. Dr Arce 37, Madrid, Spain.

Spreading depression (SD), a wave of neuron activity related to migraine and the ischaemic penumbra, features a moving shell of extracellular negative potential shift (V(o)) whose generators are poorly understood. We investigated its subcellular correlates in the hippocampal CA1 in vivo by localizing the neuron domains that generate transmembrane current (I(m)) using field analysis, and the local changes of tissue resistivity, a major determinant of extracellular current flow. A large increase of tissue resistivity occurred in times and dendritic strata displaying large V(o), albeit with different rates. Typically, SD is composed of basal and apical dendritic components. The apical SD lasts much longer, while it becomes gradually restricted to a narrow dendritic region. Strikingly, pyramidal cells displayed a strong surge of inward current only when SD affected a small dendritic region. However, when the V(o) signal covered most of the main neuron axis, only smaller surges of inward current developed at the outer dendritic rims of a wide null current zone. Computational reconstruction showed that this effect was due to strong spatial cancellation of the inward and outward currents in SD-activated isopotential and shunted regions of individual neurons. Consequently, despite former accounts of large conductance increase, the net I(m) is small and the large DeltaV(o) amplitude mostly due to increased tissue resistivity. The particular subcellular evolution indicates an initial explosive opening of conductance along most of the pyramidal neuron followed by a wave-like centripetal closure towards the apical dendrites. The applicability of these mechanisms to SD in other brain regions is discussed.
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http://dx.doi.org/10.1111/j.1460-9568.2008.06022.xDOI Listing
January 2008

A steady-state model of spreading depression predicts the importance of an unknown conductance in specific dendritic domains.

Biophys J 2007 Jun 30;92(12):4216-32. Epub 2007 Mar 30.

Cajal Institute of Neurobiology, Consejo Superior de Investigaciones Cientificas, Madrid, Spain.

Spreading depression (SD) is a pathological wave of transient neuronal inactivation. We recently reported that the characteristic sustained complete depolarization is restricted to specific cell domains where the input resistance (R(in)) first becomes negligible before achieving partial recovery, whereas in adjacent, more polarized membranes it drops by much less. The experimental study of the participating membrane channels is hindered by their mixed contribution and heterogeneous distribution. Therefore, we derived a biophysical model to analyze the conductances that replicate the subcellular profile of R(in) during SD. Systematic variation of conductance densities far beyond the ranges reported failed to fit the experimental values. Besides standard potassium, sodium, and Glu-mediated conductances, the initial opening and gradual closing of an as yet undetermined large conductance is required to account for the evolution of R(in). Potassium conductances follow in the relative contribution and their closing during the late phase is also predicted. Large intracellular potential gradients from zero to rest are readily sustained between shunted and adjacent SD-spared membranes, which remain electroregenerative. The gradients are achieved by a combination of high-conductance subcellular domains and transmembrane ion redistribution in extended but discrete dendritic domains. We conclude that the heterogeneous subcellular behavior is due to local membrane properties, some of which may be specifically activated under extreme SD conditions.
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http://dx.doi.org/10.1529/biophysj.106.090332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1877769PMC
June 2007

Noncoding RNA of U87 host gene is associated with ribosomes and is relatively resistant to nonsense-mediated decay.

Gene 2005 Dec 14;363:51-60. Epub 2005 Oct 14.

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

Non-coding RNAs are involved in many cellular processes. In particular, most of C/D box small nucleolar RNAs (snoRNAs) function as guide RNAs in site-specific 2'-O-methylation of rRNAs. While most snoRNA genes reside in introns of protein-coding genes, here we demonstrated an unusual snoRNA gene occupying an intron of a previously unknown non-protein-coding gene U87HG. We characterized this host gene in human, mouse, rat, and dog. It is a member of 5'TOP gene family, which includes many translation apparatus genes. U87HG RNA carried multiple stop-codons and was associated with ribosomes, suggesting that it may be a target for nonsense-mediated mRNA decay (NMD), a process that eliminates transcripts bearing nonsense mutations. Surprisingly, we found that U87HG RNA was hardly susceptible to NMD. Possible mechanisms (translation reinitiation, ribosomal leaky scanning, and low efficiency of translation) of this phenomenon are discussed. Unlike transcripts of four other known non-protein-coding host genes, U87HG RNA shows a relatively high degree of conservation suggesting a selective pressure and a possible functional activity of U87HG apart from producing U87 snoRNA.
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http://dx.doi.org/10.1016/j.gene.2005.08.010DOI Listing
December 2005
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