title: Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain.
abstract: Piwi-interacting RNAs (piRNAs), long thought to be restricted to germline, have recently been discovered in neurons ofAplysia, with a role in the epigenetic regulation of gene expression underlying long-term memory. We here ask whether piwi/piRNAs are also expressed and have functional roles in the mammalian brain. Large-scale RNA sequencing and subsequent analysis of protein expression revealed the presence in brain of several piRNA biogenesis factors including a mouse piwi (Mili), as well as small RNAs, albeit at low levels, resembling conserved piRNAs in mouse testes [primarily LINE1 (long interspersed nuclear element1) retrotransposon-derived]. Despite the seeming low expression of these putative piRNAs, single-base pair CpG methylation analyses across the genome of Mili/piRNA-deficient (Mili-/-) mice demonstrate that brain genomic DNA is preferentially hypomethylated within intergenic areas and LINE1 promoter areas of the genome. Furthermore,Milimutant mice exhibit behavioral deficits such as hyperactivity and reduced anxiety. These results suggest that putative piRNAs exist in mammalian brain, and similar to the role of piRNAs in testes, they may be involved in the silencing of retrotransposons, which in brain have critical roles in contributing to genomic heterogeneity underlying adaptation, stress response, and brain pathology. We also describe the presence of another class of small RNAs in the brain, with features of endogenous siRNAs, which may have taken over the role of invertebrate piRNAs in their capacity to target both transposons, as well as protein-coding genes. Thus, RNA interference through gene and retrotransposon silencing previously encountered inAplysiamay also have potential roles in the mammalian brain.
authors: Department of Neuroscience, Columbia University, New York, NY 10032.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461.|Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461.
authors: Sayan
authors: S
authors: Nandi
authors: Department of Physiology, Weill Cornell Medical College, New York, NY 10065.|Department of Biophysics and Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065.
authors: Dhruva
authors: D
authors: Chandramohan
authors: Department of Neuroscience, Columbia University, New York, NY 10032.
authors: Luana
authors: L
authors: Fioriti
authors: Department of Medicine, Weill Cornell Medical College, New York, NY 10065.|Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065.
authors: Ari M
authors: AM
authors: Melnick
authors: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461.|Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461.
authors: Jean M
authors: JM
authors: Hébert
authors: Department of Physiology, Weill Cornell Medical College, New York, NY 10065.|Department of Biophysics and Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065.|The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065.|The Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065.
authors: Christopher E
authors: CE
authors: Mason
authors: Department of Bioengineering, Stanford University, Stanford, CA 94305; priya@rockefeller.edu erk5@columbia.edu.|Laboratory for Neural Dynamics and Cognition, Rockefeller University, New York, NY 10065.
authors: Priyamvada
authors: P
authors: Rajasethupathy
authors: Department of Neuroscience, Columbia University, New York, NY 10032; priya@rockefeller.edu erk5@columbia.edu.|Howard Hughes Medical Institute, Columbia University, New York, NY 10032.|Kavli Institute for Brain Science, Columbia University, New York, NY 10032.
authors: Eric R
authors: ER
authors: Kandel
keywords: DNA methylation; behavior; endogenous siRNA; piwi-interacting RNA; transposon