microRNA and Down Syndrome

Summary

Principal Investigator: Karl H Obrietan
Abstract: The chromosome abnormality in Down syndrome (DS) results from a triplication in a portion of human chromosome 21 (Hsa21), but how this chromosomal anomaly causes the DS phenotype is not clear. The current proposal will directly address this issue, with an emphasis on a novel class of endogenous gene regulators, microRNAs (miRNAs). MiRNAs are generally regarded as negative regulators of gene expression that inhibit translation and/or promote messenger RNA (mRNA) degradation by base-pairing to complementary sequences within protein-coding mRNA transcripts. Our recent bioinformatic analyses established that Hsa21 harbors five miRNA genes. Importantly, miRNA expression profiling, miRNA RT-PCR, and miRNA in situ hybridization experiments demonstrated that all five Hsa21-derived miRNAs are over-expressed in brain and heart specimens from individuals with DS. We now hypothesize that the over-expression of the five Hsa21-derived miRNAs results in the under-expression of a number of important protein targets which contribute, in part, to the DS phenotype. Bioinformatic analyses demonstrated that several thousand proteins may be regulated by these miRNAs. Because combinatorial targeting of multiple miRNAs with a single mRNA may lead to a more pronounced down-regulation relative to mRNAs targeted by a few miRNAs, all of the Hsa21-derived miRNA/mRNA pairs were re-analyzed for the presence of multiple Hsa21-derived miRNA binding sites. This list of candidate targets was subsequently prioritized with respect to the potential clinical relevance of an individual target gene in playing a role in DS. Based on these criteria, we chose to investigate the methyl-CpG-binding protein (MeCP2), a transcription factor, as a potentially important Hsa21- derived miRNA target since its 34-untranslated region harbors at least one putative recognition site for all of the Has21-derived miRNAs. Additionally, MeCP2 is a provocative miRNA target since mutations in this gene contribute to Rett syndrome, a neurodevelopmental disorder that shares some of the neurologic abnormalities observed in DS. Our preliminary data now demonstrate that MeCP2 mRNA is a direct target of Hsa21-derived miR-155 and that MeCP2 is under-expressed in human fetal and adult DS brain specimens and in a mouse model of DS. As a consequence of attenuated MeCP2 expression, transcriptionally-activated and -silenced MeCP2 target genes are aberrantly regulated in these DS brain specimens. To begin to substantiate a causal role of Hsa21-derived miRNAs in DS, in vivo silencing of endogenous mature miR-155 expression by intra- ventricular injection of antagomir-155 resulted in the normalization of miR-155 and MeCP2 expression levels in the DS mouse brains. Taken together, these preliminary data suggest that improper repression of MeCP2, secondary to trisomic over-expression of miR-155, result in the aberrant regulation of MeCP2 target genes. This dysregulation subsequently results in the destabilization of important "regulatory circuits" that contribute, in part, to the cognitive defects that occur in DS individuals. PUBLIC HEALTH RELEVANCE: This project represents a novel line of inquiry regarding the molecular mechanisms of DS. This study will provide "proof of concept" that Hsa21-derived miRNAs inhibit the expression of critical regulatory proteins, which in turn, results in aberrant expression of a number of factors critical for neurodevelopment. Our approach includes a comprehensive and multi-disciplinary approach and includes human tissues, cell lines, and a DS mouse model. Our project will define miRNA/mRNA targets responsible for DS and will potentially lead to novel therapeutic strategies to treat DS individuals in the perinatal period to change the course of pathogenesis.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Trisomy-21 gene dosage over-expression of miRNAs results in the haploinsufficiency of specific target proteins
    Terry S Elton
    Division of Pharmacology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
    RNA Biol 7:540-7. 2010
  2. pmc Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains
    Donald E Kuhn
    College of Pharmacy, Division of Pharmacology, Ohio State University, Columbus, Ohio 43210, USA
    J Biol Chem 285:1529-43. 2010
  3. pmc Heart rate control with adrenergic blockade: clinical outcomes in cardiovascular medicine
    David Feldman
    Heart Failure Transplant and VAD Programs, Minneapolis Heart Institute, Minneapolis, Minnesota 55407, USA
    Vasc Health Risk Manag 6:387-97. 2010
  4. pmc miR-802 regulates human angiotensin II type 1 receptor expression in intestinal epithelial C2BBe1 cells
    Sarah E Sansom
    Davis Heart and Lung Research Institute, Department of Pathology, The Ohio State Univ, Columbus, 43210, USA
    Am J Physiol Gastrointest Liver Physiol 299:G632-42. 2010
  5. ncbi miRNAs got rhythm
    Terry S Elton
    Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA
    Life Sci 88:373-83. 2011
  6. pmc MicroRNA-1 and -133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex
    Andriy E Belevych
    The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America
    PLoS ONE 6:e28324. 2011

Scientific Experts

  • Terry Elton
  • David Feldman
  • Sarah E Sansom
  • Mickey M Martin
  • Andriy E Belevych
  • Gerard J Nuovo
  • Donald E Kuhn
  • Cynthia A Carnes
  • Radmila Terentyeva
  • Yukiko Kunitomo
  • Sandor Gyorke
  • Maha Abdellatif
  • Hsiang Ting Ho
  • Jennifer A Rochira
  • Dmitry Terentyev
  • Yoshinori Nishijima
  • Hitesh K Jindal
  • Adam P Pleister
  • Narasimham L Parinandi
  • Sainath R Kotha
  • Alvin V Terry
  • Geraldine E Malana
  • Elizabeth Head
  • Wayne D Beck

Detail Information

Publications6

  1. pmc Trisomy-21 gene dosage over-expression of miRNAs results in the haploinsufficiency of specific target proteins
    Terry S Elton
    Division of Pharmacology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
    RNA Biol 7:540-7. 2010
    ..We now propose that Ts21 gene dosage over-expression of Hsa21-derived miRNAs in DS individuals result in the decreased expression of specific target proteins (i.e. haploinsufficiency) that contribute, in part, to the DS phenotype...
  2. pmc Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains
    Donald E Kuhn
    College of Pharmacy, Division of Pharmacology, Ohio State University, Columbus, Ohio 43210, USA
    J Biol Chem 285:1529-43. 2010
    ..Finally these results suggest that selective inactivation of Hsa21-derived miRNAs may provide a novel therapeutic tool in the treatment of DS...
  3. pmc Heart rate control with adrenergic blockade: clinical outcomes in cardiovascular medicine
    David Feldman
    Heart Failure Transplant and VAD Programs, Minneapolis Heart Institute, Minneapolis, Minnesota 55407, USA
    Vasc Health Risk Manag 6:387-97. 2010
    ..Clinical evidence suggests that attainment of HR control is an important treatment objective for patients with cardiovascular conditions, and vasodilating beta-blocker efficacy may aid in accomplishing improved outcomes...
  4. pmc miR-802 regulates human angiotensin II type 1 receptor expression in intestinal epithelial C2BBe1 cells
    Sarah E Sansom
    Davis Heart and Lung Research Institute, Department of Pathology, The Ohio State Univ, Columbus, 43210, USA
    Am J Physiol Gastrointest Liver Physiol 299:G632-42. 2010
    ..These results suggest that miR-802 can modulate the expression of the hAT(1)R in the GI tract and ultimately play a role in regulating the biological efficacy of Ang II in this system...
  5. ncbi miRNAs got rhythm
    Terry S Elton
    Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA
    Life Sci 88:373-83. 2011
    ..In this review we summarize the basic mechanisms of action of miRNAs as they are related to cardiac arrhythmia and address the potential for miRNAs to be therapeutically manipulated in the treatment of arrhythmias...
  6. pmc MicroRNA-1 and -133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex
    Andriy E Belevych
    The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America
    PLoS ONE 6:e28324. 2011
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