Defining the messenger RNP code in the brain

Summary

Principal Investigator: EUGENE WEI MING YEO
Abstract: DESCRIPTION (provided by applicant): RNA binding proteins (RBPs) interact with functional RNA elements embedded within pre- and mature messenger RNA to form messenger ribonucleoprotein (mRNP) complexes. These interactions result in the faithful execution of RNA processing events such as pre-mRNA alternative splicing, RNA stability and translational control. Aberrant alterations in the interactions between the RBPs and their RNA elements ultimately lead to behavioral abnormalities and neurological developmental defects, which can often manifest as fatal diseases such as Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis or life-long debilitating behavioral abnormalities such as Prader-Willi/Angelman Syndromes, Schizophrenia and Autism Spectrum Disorder. These findings underscore the importance of investigating the roles of these RBPs in the brain. In particular, our project is aimed at systematically, using genome-wide biochemical and bioinformatic assays, identifying the functional RNA elements that are recognized by RBPs in mouse brain and human neurons. We will develop a novel resource of human pluripotent stem cells stably expressing tagged RBPs that can be differentiated into human neurons. This will enable the identification of RNA binding sites of 50 RBPs in human neural RNAs in a uniform and systematic manner using cutting-edge genomic approaches such as cross-linking and immunoprecipitation followed by high-throughput sequencing (CLIP- seq). To reveal the splicing, stability, and translational changes that are dependent on direct binding of these RBPs we will perform high-throughput sequencing of mRNAs (RNA-seq) and ribosome-protected fragments (RPFs). Finally, we will leverage our computational expertise to build predictive models using this genome-wide, multi-scale, mRNP code in the brain.
Funding Period: 2012-02-15 - 2017-01-31
more information: NIH RePORT

Top Publications

  1. pmc Misregulated RNA processing in amyotrophic lateral sclerosis
    Magdalini Polymenidou
    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093 6070, USA
    Brain Res 1462:3-15. 2012
  2. pmc Early specification of CD8+ T lymphocyte fates during adaptive immunity revealed by single-cell gene-expression analyses
    Janilyn Arsenio
    1 Department of Medicine, University of California San Diego, La Jolla, California, USA 2
    Nat Immunol 15:365-72. 2014
  3. pmc The dsRBP and inactive editor ADR-1 utilizes dsRNA binding to regulate A-to-I RNA editing across the C. elegans transcriptome
    Michael C Washburn
    Department of Biology, Indiana University, Bloomington, IN 47405, USA
    Cell Rep 6:599-607. 2014
  4. pmc Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges
    Michael T Lovci
    1 Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA 2 Stem Cell Program, University of California, San Diego, La Jolla, California, USA 3 Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA
    Nat Struct Mol Biol 20:1434-42. 2013
  5. pmc Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment
    Wenqing Cai
    Sanford Burnham Medical Research Institute, La Jolla, California 92037, USA
    Genes Dev 27:2332-44. 2013
  6. pmc Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration
    Clotilde Lagier-Tourenne
    Departments of Neurosciences, Cellular and Molecular Medicine, and Pathology, and Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093
    Proc Natl Acad Sci U S A 110:E4530-9. 2013
  7. pmc Differential L1 regulation in pluripotent stem cells of humans and apes
    Maria C N Marchetto
    1 Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA 2
    Nature 503:525-9. 2013
  8. pmc Reactivation of fetal splicing programs in diabetic hearts is mediated by protein kinase C signaling
    Sunil K Verma
    From the Departments of Biochemistry and Molecular Biology and
    J Biol Chem 288:35372-86. 2013
  9. pmc Meclizine inhibits mitochondrial respiration through direct targeting of cytosolic phosphoethanolamine metabolism
    Vishal M Gohil
    From the Departments of Molecular Biology and Medicine, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114
    J Biol Chem 288:35387-95. 2013
  10. pmc Functional genomic analysis of the let-7 regulatory network in Caenorhabditis elegans
    Shaun E Hunter
    Division of Biology, University of California San Diego, La Jolla, California, United States of America
    PLoS Genet 9:e1003353. 2013

Research Grants

  1. NINDS Center Core for Brain Imaging
    DANIEL SCOTT MARCUS; Fiscal Year: 2013

Detail Information

Publications17

  1. pmc Misregulated RNA processing in amyotrophic lateral sclerosis
    Magdalini Polymenidou
    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093 6070, USA
    Brain Res 1462:3-15. 2012
    ..Hence, ALS and FTLD converge in pathogenic pathways disrupting the regulation of RNA processing. This article is part of a Special Issue entitled RNA-Binding Proteins...
  2. pmc Early specification of CD8+ T lymphocyte fates during adaptive immunity revealed by single-cell gene-expression analyses
    Janilyn Arsenio
    1 Department of Medicine, University of California San Diego, La Jolla, California, USA 2
    Nat Immunol 15:365-72. 2014
    ..Our findings emphasize the importance of single-cell analyses in understanding fate determination and provide new insights into the specification of divergent lymphocyte fates early during an immune response to microbial infection. ..
  3. pmc The dsRBP and inactive editor ADR-1 utilizes dsRNA binding to regulate A-to-I RNA editing across the C. elegans transcriptome
    Michael C Washburn
    Department of Biology, Indiana University, Bloomington, IN 47405, USA
    Cell Rep 6:599-607. 2014
    ..These results raise the possibility that other dsRNA binding proteins, including the inactive human ADARs, regulate RNA editing through deaminase-independent mechanisms. ..
  4. pmc Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges
    Michael T Lovci
    1 Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA 2 Stem Cell Program, University of California, San Diego, La Jolla, California, USA 3 Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA
    Nat Struct Mol Biol 20:1434-42. 2013
    ..Thus we demonstrate a previously unknown RNA-mediated mechanism for AS control by distally bound RNA-binding proteins. ..
  5. pmc Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment
    Wenqing Cai
    Sanford Burnham Medical Research Institute, La Jolla, California 92037, USA
    Genes Dev 27:2332-44. 2013
    ..This is the first demonstration that cues from the progenitor cell environment direct the subunit variant composition of SWI/SNF to remodel the transcriptional landscape for lineage-specific differentiation...
  6. pmc Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration
    Clotilde Lagier-Tourenne
    Departments of Neurosciences, Cellular and Molecular Medicine, and Pathology, and Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093
    Proc Natl Acad Sci U S A 110:E4530-9. 2013
    ..Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions. ..
  7. pmc Differential L1 regulation in pluripotent stem cells of humans and apes
    Maria C N Marchetto
    1 Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA 2
    Nature 503:525-9. 2013
    ..We propose that differences in L1 mobility may have differentially shaped the genomes of humans and NHPs and could have continuing adaptive significance. ..
  8. pmc Reactivation of fetal splicing programs in diabetic hearts is mediated by protein kinase C signaling
    Sunil K Verma
    From the Departments of Biochemistry and Molecular Biology and
    J Biol Chem 288:35372-86. 2013
    ..These findings provide a basis for PKC-mediated cardiac pathogenesis under diabetic conditions. ..
  9. pmc Meclizine inhibits mitochondrial respiration through direct targeting of cytosolic phosphoethanolamine metabolism
    Vishal M Gohil
    From the Departments of Molecular Biology and Medicine, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114
    J Biol Chem 288:35387-95. 2013
    ....
  10. pmc Functional genomic analysis of the let-7 regulatory network in Caenorhabditis elegans
    Shaun E Hunter
    Division of Biology, University of California San Diego, La Jolla, California, United States of America
    PLoS Genet 9:e1003353. 2013
    ..Overall, a complex network of genes with various activities is subject to let-7 regulation to coordinate developmental timing across tissues during worm development...
  11. pmc ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43
    Eveline S Arnold
    Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA
    Proc Natl Acad Sci U S A 110:E736-45. 2013
    ..Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage...
  12. pmc Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome
    Christopher Vollmers
    Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
    Cell Metab 16:833-45. 2012
    ..The results offer a framework for understanding the dynamics of metabolism, circadian clock, and chromatin modifications involved in metabolic homeostasis...
  13. pmc Genome-wide approaches to dissect the roles of RNA binding proteins in translational control: implications for neurological diseases
    Katannya Kapeli
    Department of Cellular and Molecular Medicine, University of California San Diego La Jolla, CA, USA
    Front Neurosci 6:144. 2012
    ....
  14. pmc Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs
    Clotilde Lagier-Tourenne
    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California, USA
    Nat Neurosci 15:1488-97. 2012
    ....
  15. pmc LIN28 binds messenger RNAs at GGAGA motifs and regulates splicing factor abundance
    Melissa L Wilbert
    Department of Cellular and Molecular Medicine, Stem Cell Program and Institute for Genomic Medicine, University of California, San Diego, CA, USA
    Mol Cell 48:195-206. 2012
    ..Splicing-sensitive microarrays demonstrated that exogenous LIN28 expression causes widespread downstream alternative splicing changes. These findings identify important regulatory functions of LIN28 via direct mRNA interactions...
  16. pmc Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins
    Stephanie C Huelga
    Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA
    Cell Rep 1:167-78. 2012
    ..Our findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells...
  17. pmc The Period protein homolog LIN-42 negatively regulates microRNA biogenesis in C. elegans
    Priscilla M Van Wynsberghe
    Division of Biology, University of California at San Diego, La Jolla, CA 92093 0349, USA Department of Biology, Colgate University, Hamilton, NY 13323, USA Electronic address
    Dev Biol 390:126-35. 2014
    ..Furthermore, small RNA-seq analysis showed widespread increases in the levels of mature miRNAs in lin-42 mutants. Thus, we propose that the period protein homolog LIN-42 is a global regulator of miRNA biogenesis. ..

Research Grants30

  1. NINDS Center Core for Brain Imaging
    DANIEL SCOTT MARCUS; Fiscal Year: 2013
    ..The NCCBI will include Administration, Informatics, and Analysis cores to achieve these aims. ..