Browsing by Subject "TRANSCRIPTION"

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  • Lemmelä, Susanna; Solovieva, Svetlana; Shiri, Rahman; Benner, Christian; Heliovaara, Markku; Kettunen, Johannes; Anttila, Verneri; Ripatti, Samuli; Perola, Markus; Seppala, Ilkka; Juonala, Markus; Kahonen, Mika; Salomaa, Veikko; Viikari, Jorma; Raitakari, Olli T.; Lehtimaki, Terho; Palotie, Aarno; Viikari-Juntura, Eira; Husgafvel-Pursiainen, Kirsti (2016)
    Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p
  • Bompada, Pradeep; Atac, David; Luan, Cheng; Andersson, Robin; Omella, Judit Domenech; Laakso, Emilia Ottosson; Wright, Jason; Groop, Leif; De Marinis, Yang (2016)
    Thioredoxin-interacting protein (TXNIP) has been shown to be associated with glucose-induced deterioration of pancreatic beta cell function in diabetes. However, whether epigenetic mechanisms contribute to the regulation of TXNIP gene expression by glucose is not clear. Here we studied how glucose exerts its effect on TXNIP gene expression via modulation of histone acetylation marks. To achieve this, we applied clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) to knock out his tone acetyltransferase (HAT) p300 in a rat pancreatic beta cell line INS1 832/13. We also treated the cells and human islets with chemical inhibitors of HAT p300 and histone deacetylase (HDAC). In human islets, diabetes and high glucose resulted in elevated TXNIP and EP300 expression, and glucose-induced TXNIP expression could be reversed by p300 inhibitor C646. In INS1 832/13 cells, Ep300 knock-out by CRISPR/Cas9 elevated glucose-induced insulin secretion and greatly reduced glucose-stimulated Txnip expression and cell apoptosis. This effect could be ascribed to decrease in histone marks H3K9ac and H4ac at the promoter and first coding region of the Txnip gene. Histone marks H3K9ac and H4ac in the Txnip gene in the wild-type cells was inhibited by HDAC inhibitor at high glucose, which most likely was due to enhanced acetylation levels of p300 after HDAC inhibition; and thereby reduced p300 binding to the Txnip gene promoter region. Such inhibition was absent in the Ep300 knock-out cells. Our study provides evidence that histone acetylation serves as a key regulator of glucose-induced increase in TXNIP gene expression and thereby glucotoxicity-induced apoptosis. (C) 2016 Elsevier Ltd. All rights reserved.
  • Miikkulainen, Petra; Högel, Heidi; Seyednasrollah, Fatemeh; Rantanen, Krista; Elo, Laura L.; Jaakkola, Panu M. (2019)
    Most clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), resulting in the accumulation of hypoxia-inducible factor -subunits (HIF-) and their downstream targets. HIF-2 expression is particularly high in ccRCC and is associated with increased ccRCC growth and aggressiveness. In the canonical HIF signaling pathway, HIF-prolyl hydroxylase 3 (PHD3) suppresses HIF-2 protein by post-translational hydroxylation under sufficient oxygen availability. Here, using immunoblotting and immunofluorescence staining, qRT-PCR, and siRNA-mediated gene silencing, we show that unlike in the canonical pathway, PHD3 silencing in ccRCC cells leads to down-regulation of HIF-2 protein and mRNA. Depletion of other PHD family members had no effect on HIF-2 expression, and PHD3 knockdown in non-RCC cells resulted in the expected increase in HIF-2 protein expression. Accordingly, PHD3 knockdown decreased HIF-2 target gene expression in ccRCC cells and expression was restored upon forced HIF-2 expression. The effect of PHD3 depletion was pinpointed to HIF2A mRNA stability. In line with these in vitro results, a strong positive correlation of PHD3 and HIF2A mRNA expression in ccRCC tumors was detected. Our results suggest that in contrast to the known negative regulation of HIF-2 in most cell types, high PHD3 expression in ccRCC cells maintains elevated HIF-2 expression and that of its target genes, which may enhance kidney cancer aggressiveness.
  • Poranen, Minna M.; Mäntynen, Sari; ICTV Report Consortium (2017)
    The family Cystoviridae includes enveloped viruses with a tri-segmented dsRNA genome and a double-layered protein capsid. The innermost protein shell is a polymerase complex responsible for genome packaging, replication and transcription. Cystoviruses infect Gram-negative bacteria, primarily plant-pathogenic Pseudomonas syringae strains. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Cystoviridae, which is available at http://www. ictv. global/report/cystoviridae.
  • Parri, Elina; Kuusanmäki, Heikki; van Adrichem, Arjan J.; Kaustio, Meri; Wennerberg, Krister (2020)
    STAT3 mediates signalling downstream of cytokine and growth factor receptors where it acts as a transcription factor for its target genes, including oncogenes and cell survival regulating genes. STAT3 has been found to be persistently activated in many types of cancers, primarily through its tyrosine phosphorylation (Y705). Here, we show that constitutive STAT3 activation protects cells from cytotoxic drug responses of several drug classes. To find novel and potentially targetable STAT3 regulators we performed a kinase and phosphatase siRNA screen with cells expressing either a hyperactive STAT3 mutant or IL6-induced wild type STAT3. The screen identified cell division cycle 7-related protein kinase (CDC7), casein kinase 2, alpha 1 (CSNK2), discoidin domain-containing receptor 2 (DDR2), cyclin-dependent kinase 8 (CDK8), phosphatidylinositol 4-kinase 2-alpha (PI4KII), C-terminal Src kinase (CSK) and receptor-type tyrosine-protein phosphatase H (PTPRH) as potential STAT3 regulators. Using small molecule inhibitors targeting these proteins, we confirmed dose and time dependent inhibition of STAT3-mediated transcription, suggesting that inhibition of these kinases may provide strategies for dampening STAT3 activity in cancers.
  • Ross, Jacob A.; Levy, Yotam; Ripolone, Michela; Kolb, Justin S.; Turmaine, Mark; Holt, Mark; Lindqvist, Johan; Claeys, Kristl G.; Weis, Joachim; Monforte, Mauro; Tasca, Giorgio; Moggio, Maurizio; Figeac, Nicolas; Zammit, Peter S.; Jungbluth, Heinz; Fiorillo, Chiara; Vissing, John; Witting, Nanna; Granzier, Henk; Zanoteli, Edmar; Hardeman, Edna C.; Wallgren-Pettersson, Carina; Ochala, Julien (2019)
    Nemaline myopathy (NM) is a skeletal muscle disorder caused by mutations in genes that are generally involved in muscle contraction, in particular those related to the structure and/or regulation of the thin filament. Many pathogenic aspects of this disease remain largely unclear. Here, we report novel pathological defects in skeletal muscle fibres of mouse models and patients with NM: irregular spacing and morphology of nuclei; disrupted nuclear envelope; altered chromatin arrangement; and disorganisation of the cortical cytoskeleton. Impairments in contractility are the primary cause of these nuclear defects. We also establish the role of microtubule organisation in determining nuclear morphology, a phenomenon which is likely to contribute to nuclear alterations in this disease. Our results overlap with findings in diseases caused directly by mutations in nuclear envelope or cytoskeletal proteins. Given the important role of nuclear shape and envelope in regulating gene expression, and the cytoskeleton in maintaining muscle fibre integrity, our findings are likely to explain some of the hallmarks of NM, including contractile filament disarray, altered mechanical properties and broad transcriptional alterations.
  • Palmroth, Maaria; Viskari, Hanna; Seppänen, Mikko R. J.; Keskitalo, Salla; Virtanen, Anniina; Varjosalo, Markku; Silvennoinen, Olli; Isomäki, Pia (2021)
    Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional coregulator that has an important role in the regulation of the immune response. IRF2BP2 has been associated with the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway, but its exact role remains elusive. Here, we identified a novel clinical variant, IRF2BP2 c.625_665del, from two members of a family with inflammatory conditions and investigated the function of IRF2BP2 and c.625_665del mutation in JAK-STAT pathway activation and inflammatory signaling. The levels of constitutive and cytokine-induced phosphorylation of STATs and total STAT1 in peripheral blood monocytes, T cells, and B cells from the patients and four healthy controls were measured by flow cytometry. Inflammation-related gene expression was studied in peripheral blood mononuclear cells using direct digital detection of mRNA (NanoString). Finally, we studied the relationship between IRF2BP2 and STAT1 activation using a luciferase reporter system in a cell model. Our results show that patients having the IRF2BP2 c.625_665del mutation presented overexpression of STAT1 protein and increased constitutive activation of STAT1. In addition, interferon-induced JAK-STAT signaling was upregulated, and several interferon-inducible genes were overexpressed. Constitutive phosphorylation of STAT5 was also found to be upregulated in CD4(+) T cells from the patients. Using a cell model, we show that IRF2BP2 was needed to attenuate STAT1 transcriptional activity and that IRF2BP2 c.625_665del mutation failed in this. We conclude that IRF2BP2 has an important role in suppressing immune responses elicited by STAT1 and STAT5 and suggest that aberrations in IRF2BP2 can lead to abnormal function of intrinsic immunity.
  • Ylikallio, Emil; Woldegebriel, Rosa; Tumiati, Manuela; Isohanni, Pirjo; Ryan, Monique M.; Stark, Zornitza; Walsh, Maie; Sawyer, Sarah L.; Bell, Katrina M.; Oshlack, Alicia; Lockhart, Paul J.; Shcherbii, Mariia; Estrada-Cuzcano, Alejandro; Atkinson, Derek; Hartley, Taila; Tetreault, Martine; Cuppen, Inge; van der Pol, W. Ludo; Candayan, Ayse; Battaloglu, Esra; Parman, Yesim; van Gassen, Koen L. I.; van den Boogaard, Marie-Jose H.; Boycott, Kym M.; Kauppi, Liisa; Jordanova, Albena; Lonnqvist, Tuula; Tyynismaa, Henna (2017)
    Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.
  • van Leeuwen, Elisabeth M.; Sabo, Aniko; Bis, Joshua C.; Huffman, Jennifer E.; Manichaikul, Ani; Smith, Albert V.; Feitosa, Mary F.; Demissie, Serkalem; Joshi, Peter K.; Duan, Qing; Marten, Jonathan; van Klinken, Jan B.; Surakka, Ida; Nolte, Ilja M.; Zhang, Weihua; Mbarek, Hamdi; Li-Gao, Ruifang; Trompet, Stella; Verweij, Niek; Evangelou, Evangelos; Lyytikainen, Leo-Pekka; Tayo, Bamidele O.; Deelen, Joris; van der Most, Peter J.; van der Laan, Sander W.; Arking, Dan E.; Morrison, Alanna; Dehghan, Abbas; Franco, Oscar H.; Hofman, Albert; Rivadeneira, Fernando; Sijbrands, Eric J.; Uitterlinden, Andre G.; Mychaleckyj, Josyf C.; Campbell, Archie; Hocking, Lynne J.; Padmanabhan, Sandosh; Brody, Jennifer A.; Rice, Kenneth M.; White, Charles C.; Harris, Tamara; Isaacs, Aaron; Campbell, Harry; Lange, Leslie A.; Rudan, Igor; Kolcic, Ivana; Navarro, Pau; Zemunik, Tatijana; Salomaa, Veikko; Ripatti, Samuli; CHARGE Lipids Working Grp (2016)
    Background So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from similar to 60 000 individuals in the discovery stage and similar to 90 000 samples in the replication stage. Results Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. Conclusions This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.
  • Kontio, Juho A. J.; Pyhäjärvi, Tanja; Sillanpää, Mikko J. (2021)
    Author summary Here we built up a mathematically justified bridge between 1) parametric approaches and 2) co-expression networks in light of identifying molecular interactions underlying complex traits. We first shared our concern that methodological improvements around these schemes, adjusting only their power and scalability, are bounded by more fundamental scheme-specific limitations. Subsequently, our theoretical results were exploited to overcome these limitations to find gene-by-gene interactions neither of which can capture alone. We also aimed to illustrate how this framework enables the interpretation of co-expression networks in a more parametric sense to achieve systematic insights into complex biological processes more reliably. The main procedure was fit for various types of biological applications and high-dimensional data to cover the area of systems biology as broadly as possible. In particular, we chose to illustrate the method's applicability for gene-profile based risk-stratification in cancer research using public acute myeloid leukemia datasets. A wide variety of 1) parametric regression models and 2) co-expression networks have been developed for finding gene-by-gene interactions underlying complex traits from expression data. While both methodological schemes have their own well-known benefits, little is known about their synergistic potential. Our study introduces their methodological fusion that cross-exploits the strengths of individual approaches via a built-in information-sharing mechanism. This fusion is theoretically based on certain trait-conditioned dependency patterns between two genes depending on their role in the underlying parametric model. Resulting trait-specific co-expression network estimation method 1) serves to enhance the interpretation of biological networks in a parametric sense, and 2) exploits the underlying parametric model itself in the estimation process. To also account for the substantial amount of intrinsic noise and collinearities, often entailed by expression data, a tailored co-expression measure is introduced along with this framework to alleviate related computational problems. A remarkable advance over the reference methods in simulated scenarios substantiate the method's high-efficiency. As proof-of-concept, this synergistic approach is successfully applied in survival analysis, with acute myeloid leukemia data, further highlighting the framework's versatility and broad practical relevance.
  • Heinrichs, Stefan; Conover, Lillian F.; Bueso-Ramos, Carlos E.; Kilpivaara, Outi; Stevenson, Kristen; Neuberg, Donna; Loh, Mignon L.; Wu, Wen-Shu; Rodig, Scott J.; Garcia-Manero, Guillermo; Kantarjian, Hagop M.; Look, A. Thomas (2013)
  • Viita, Tiina; Kyheroinen, Salla; Prajapati, Bina; Virtanen, Jori; Frilander, Mikko J.; Varjosalo, Markku; Vartiainen, Maria K. (2019)
    In addition to its essential functions within the cytoskeleton, actin also localizes to the cell nucleus, where it is linked to many important nuclear processes from gene expression to maintenance of genomic integrity. However, the molecular mechanisms by which actin operates in the nucleus remain poorly understood. Here, we have used two complementary mass spectrometry (MS) techniques, AP-MS and BioID, to identify binding partners for nuclear actin. Common high-confidence interactions highlight the role of actin in chromatin-remodeling complexes and identify the histone-modifying complex human Ada-Two-A-containing (hATAC) as a novel actin-containing nuclear complex. Actin binds directly to the hATAC subunit KAT14, and modulates its histone acetyl transferase activity in vitro and in cells. Transient interactions detected through BioID link actin to several steps of transcription as well as to RNA processing. Alterations in nuclear actin levels disturb alternative splicing in minigene assays, likely by affecting the transcription elongation rate. This interactome analysis thus identifies both novel direct binding partners and functional roles for nuclear actin, as well as forms a platform for further mechanistic studies on how actin operates during essential nuclear processes. This article has an associated First Person interview with the first author of the paper.
  • Lippert, Timothy P.; Marzec, Paulina; Idilli, Aurora I.; Sarek, Grzegorz; Vancevska, Aleksandra; Bower, Mark; Farrell, Paul J.; Ojala, Päivi M.; Feldhahn, Niklas; Boulton, Simon J. (2021)
    To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. similar to 85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining similar to 15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi's sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours. similar to 15% of cancers induce alternative lengthening of telomeres (ALT) to activate telomere maintenance. Here, the authors reveal that infection with Kaposi's sarcoma herpesvirus (KSHV) induces acquisition of ALT-like features in previously non-ALT cell lines.
  • Nair, Vidhya A.; Valo, Satu; Peltomäki, Päivi; Bajbouj, Khuloud; Abdel-Rahman, Wael M. (2020)
    There is an ample epidemiological evidence to support the role of environmental contaminants such as bisphenol A (BPA) in breast cancer development but the molecular mechanisms of their action are still not fully understood. Therefore, we sought to analyze the effects of three common contaminants (BPA; 4-tert-octylphenol, OP; hexabromocyclododecane, HBCD) on mammary epithelial cell (HME1) and MCF7 breast cancer cell line. We also supplied some data on methoxychlor, MXC; 4-nonylphenol, NP; and 2-amino-1-methyl-6-phenylimidazo [4-b] pyridine, PhIP. We focused on testing the prolonged (two months) exposure to low nano-molar concentrations (0.0015-0.0048 nM) presumed to be oncogenic and found that they induced DNA damage (evidenced by upregulation of pH2A.X, pCHK1, pCHK2, p-P53) and disrupted the cell cycle. Some agents induced epigenetic (methylation) changes of tumor suppressor genes TIMP3, CHFR, ESR1, IGSF4, CDH13, and GSTP1. Obviously, the accumulation of these molecular alterations is an essential base for cancer development. Consistent with this, we observed that these agents increased cellular invasiveness through collagen. Cellular abilities to form colonies in soft agar were increased for MCF7. Toxic agents induced phosphorylation of protein kinase such as EGFR, CREB, STAT6, c-Jun, STAT3, HSP6, HSP27, AMPK alpha 1, FAK, p53, GSK-3 alpha/beta, and P70S6 in HME1. Most of these proteins are involved in potential oncogenic pathways. Overall, these data clarify the molecular alterations that can be induced by some common environmental contaminants in mammary epithelial cells which could be a foundation to understand environmental carcinogenesis.
  • Merkin, Jason J.; Chen, Ping; Alexis, Maria S.; Hautaniemi, Sampsa K.; Burge, Christopher B. (2015)
    Mammalian genes are composed of exons, but the evolutionary origins and functions of new internal exons are poorly understood. Here, we analyzed patterns of exon gain using deep cDNA sequencing data from five mammals and one bird, identifying thousands of species-and lineage-specific exons. Most new exons derived from unique rather than repetitive intronic sequence. Unlike exons conserved across mammals, species-specific internal exons were mostly located in 5' UTRs and alternatively spliced. They were associated with upstream intronic deletions, increased nucleosome occupancy, and RNA polymerase II pausing. Genes containing new internal exons had increased gene expression, but only in tissues in which the exon was included. Increased expression correlated with the level of exon inclusion, promoter proximity, and signatures of cotranscriptional splicing. Altogether, these findings suggest that increased splicing at the 5' ends of genes enhances expression and that changes in 5' end splicing alter gene expression between tissues and between species.
  • Wan, Xing; Hendrix, Hanne; Skurnik, Mikael; Lavigne, Rob (2021)
    The deeply intertwined evolutionary history between bacteriophages and bacteria has endowed phages with highly specific mechanisms to hijack bacterial cell metabolism for their propagation. Here, we present a comprehensive, phage-driven strategy to reveal novel antibacterial targets by the exploitation of phage-bacteria interactions. This strategy will enable the design of small molecules, which mimic the inhibitory phage proteins, and allow the subsequent hit-to-lead development of these antimicrobial compounds. This proposed small molecule approach is distinct from phage therapy and phage enzyme-based antimicrobials and may produce a more sustainable generation of new antibiotics that exploit novel bacterial targets and act in a pathogen-specific manner.
  • George, Joel Johnson; Oittinen, Mikko; Martin-Diaz, Laura; Zapilko, Veronika; Iqbal, Sharif; Rintakangas, Terhi; Martins, Fabio Tadeu Arrojo; Niskanen, Henri; Katajisto, Pekka; Kaikkonen, Minna U.; Viiri, Keijo (2021)
    BACKGROUND & AIMS: Microfold cells (M cells) are immunosurveillance epithelial cells located in the Peyer's patches (PPs) in the intestine and are responsible for monitoring and transcytosis of antigens, microorganisms, and pathogens. Mature M cells use the receptor glycoprotein 2 (GP2) to aid in transcytosis. Recent studies have shown transcription factors, Spi-B and SRY-Box Transcription Factor 8 (Sox8). are necessary for M-cell differentiation, but not sufficient. An exhaustive set of factors sufficient for differentiation and development of a mature GP2+ M cell remains elusive. Our aim was to understand the role of polycomb repressive complex 2 (PRC2) as an epigenetic regulator of M-cell development. Estrogen-related-receptor gamma (Esrrg), identified as a PRC2-regulated gene, was studied in depth, in addition to its relationship with Spi-B and Sox8. METHODS: Comparative chromatin immunoprecipitation and global run-on sequencing analysis of mouse intestinal organoids were performed in stem condition, enterocyte conditions, and receptor activator of nuclear factor kappa B ligand-induced M-cell condition. Esrrg, which was identified as one of the PRC2-regulated transcription factors, was studied in wild-type mice and knocked out in intestinal organoids using guide RNA's. Sox8 null mice were used to study Esrrg and its relation to Sox8. RESULTS: chromatin immunoprecipitation and global run-on sequencing analysis showed 12 novel PRC2 regulated transcription factors, PRC2-regulated Esrrg is a novel M-cell-specific transcription factor acting on a receptor activator of nuclear factor kappa B ligand-receptor activator of nuclear factor kappa B-induced nuclear factor-kappa B pathway, upstream of Sox8, and necessary but not sufficient for a mature M-cell marker of Gp2 expression. CONCLUSIONS: PRC2 regulates a significant set of genes in M cells including Esrrg, which is critical for M-cell development and differentiation. Loss of Esrrg led to an immature M-cell phenotype lacking in Sox8 and Gp2 expression. Transcript profiling: the data have been deposited in the NCBI Gene Expression Omnibus database (GSE157629).
  • Int Cannabis Consortium; Marees, Andries T.; Gamazon, Eric R.; Gerring, Zachary; Loukola, Anu; Korhonen, Tellervo; Qaiser, Beenish; Kaprio, Jaakko (2020)
    Background: Little is known about the functional mechanisms through which genetic loci associated with substance use traits ascertain their effect. This study aims to identify and functionally annotate loci associated with substance use traits based on their role in genetic regulation of gene expression. Methods: We evaluated expression Quantitative Trait Loci (eQTLs) from 13 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database, and from whole blood of the Depression Genes and Networks (DGN) database. The role of single eQTLs was examined for six substance use traits: alcohol consumption (N = 537,349), cigarettes per day (CPD; N = 263,954), former vs. current smoker (N = 312,821), age of smoking initiation (N = 262,990), ever smoker (N = 632,802), and cocaine dependence (N = 4,769). Subsequently, we conducted a gene level analysis of gene expression on these substance use traits using S-PrediXcan. Results: Using an FDR-adjusted p-value <0.05 we found 2,976 novel candidate genetic loci for substance use traits, and identified genes and tissues through which these loci potentially exert their effects. Using S-PrediXcan, we identified significantly associated genes for all substance traits. Discussion: Annotating genes based on transcriptomic regulation improves the identification and functional characterization of candidate loci and genes for substance use traits.
  • Dzida, Tomasz; Iqbal, Mudassar; Charapitsa, Iryna; Reid, George; Stunnenberg, Henk; Matarese, Filomena; Grote, Korbinian; Honkela, Antti; Rattray, Magnus (2017)
    We have developed a machine learning approach to predict stimulation-dependent enhancer-promoter interactions using evidence from changes in genomic protein occupancy over time. The occupancy of estrogen receptor alpha (ER), RNA poly- merase (Pol II) and histone marks H2AZ and H3K4me3 were measured over time using ChIP-Seq experiments in MCF7 cells stimulated with estrogen. A Bayesian classifier was developed which uses the correlation of temporal binding patterns at enhancers and promoters and genomic proximity as features to predict interactions. This method was trained using experimentally determined interactions from the same system and was shown to achieve much higher precision than predictions based on the genomic proximity of nearest ER binding. We use the method to identify a genome-wide confident set of ER target genes and their regulatory enhancers genome- wide. Validation with publicly available GRO-Seq data demonstrates that our predicted targets are much more likely to show early nascent transcription than predictions based on genomic ER binding proximity alone.
  • Hyrskyluoto, Alise; Vartiainen, Maria K. (2020)
    Actin has essential functions both in the cytoplasm and in the nucleus, where it has been linked to key nuclear processes, from transcription to DNA damage response. The multifunctional nature of actin suggests that the cell must contain mechanisms to accurately control the cellular actin balance. Indeed, recent results have demonstrated that nuclear actin levels fluctuate to regulate the transcriptional activity of the cell and that controlled nuclear actin polymerization is required for transcription activation, cell cycle progression, and DNA repair. Intriguingly, aberrant nuclear actin regulation has been observed, for example, in cancer, signifying the importance of this process for cellular homeostasis. This review discussed the latest research on how nuclear actin is regulated, and how this influences actin-dependent nuclear processes.