Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human down syndrome brains

Donald E. Kuhn, Gerard J. Nuovo, Alvin V Terry, Mickey M. Martin, Geraldine E. Malana, Sarah E. Sansom, Adam P. Pleister, Wayne D. Beck, Elizabeth Head, David S. Feldman, Terry S. Elton

Research output: Contribution to journalArticle

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Abstract

Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. Bioinformatic annotation has established that human chromosome 21 (Hsa21) harbors five microRNA (miRNAs) genes: miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. Our laboratory recently demonstrated that Hsa21-derived miRNAs are overexpressed in DS brain and heart specimens. The aim of this study was to identify important Hsa21-derived miRNA/mRNA target pairs that may play a role, in part, in mediating the DS phenotype.Wedemonstrate by luciferase/target mRNA 3′-untranslated region reporter assays, and gain- and loss-of-function experiments that miR-155 and -802 can regulate the expression of the predicted mRNA target, the methyl-CpG-binding protein (MeCP2). We also demonstrate that MeCP2 is under-expressed in DS brain specimens isolated from either humans or mice. We further demonstrate that, as a consequence of attenuated MeCP2 expression, transcriptionally activated and silenced MeCP2 target genes, CREB1/Creb1 and MEF2C/Mef2c, are also aberrantly expressed in these DS brain specimens. Finally, in vivo silencing of endogenous miR-155 or -802, by antagomir intraventricular injection, resulted in the normalization of MeCP2 and MeCP2 target gene expression. Taken together, these results suggest that improper repression of MeCP2, secondary to trisomic overexpression of Hsa21-derived miRNAs, may contribute, in part, to the abnormalities in the neurochemistry observed in the brains of DS individuals. Finally these results suggest that selective inactivation of Hsa21-derived miRNAs may provide a novel therapeutic tool in the treatment of DS.

Original languageEnglish (US)
Pages (from-to)1529-1543
Number of pages15
JournalJournal of Biological Chemistry
Volume285
Issue number2
DOIs
StatePublished - Jan 19 2010

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Chromosomes, Human, Pair 21
Chromosomes
Down Syndrome
MicroRNAs
Brain
Proteins
Messenger RNA
Genes
3' Untranslated Regions
Bioinformatics
Ports and harbors
Luciferases
Gene expression
Intraventricular Injections
Assays
Neurochemistry
Carrier Proteins
Congenital Heart Defects
Human Chromosomes
Computational Biology

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human down syndrome brains. / Kuhn, Donald E.; Nuovo, Gerard J.; Terry, Alvin V; Martin, Mickey M.; Malana, Geraldine E.; Sansom, Sarah E.; Pleister, Adam P.; Beck, Wayne D.; Head, Elizabeth; Feldman, David S.; Elton, Terry S.

In: Journal of Biological Chemistry, Vol. 285, No. 2, 19.01.2010, p. 1529-1543.

Research output: Contribution to journalArticle

Kuhn, DE, Nuovo, GJ, Terry, AV, Martin, MM, Malana, GE, Sansom, SE, Pleister, AP, Beck, WD, Head, E, Feldman, DS & Elton, TS 2010, 'Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human down syndrome brains', Journal of Biological Chemistry, vol. 285, no. 2, pp. 1529-1543. https://doi.org/10.1074/jbc.M109.033407
Kuhn, Donald E. ; Nuovo, Gerard J. ; Terry, Alvin V ; Martin, Mickey M. ; Malana, Geraldine E. ; Sansom, Sarah E. ; Pleister, Adam P. ; Beck, Wayne D. ; Head, Elizabeth ; Feldman, David S. ; Elton, Terry S. / Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human down syndrome brains. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 2. pp. 1529-1543.
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abstract = "Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. Bioinformatic annotation has established that human chromosome 21 (Hsa21) harbors five microRNA (miRNAs) genes: miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. Our laboratory recently demonstrated that Hsa21-derived miRNAs are overexpressed in DS brain and heart specimens. The aim of this study was to identify important Hsa21-derived miRNA/mRNA target pairs that may play a role, in part, in mediating the DS phenotype.Wedemonstrate by luciferase/target mRNA 3′-untranslated region reporter assays, and gain- and loss-of-function experiments that miR-155 and -802 can regulate the expression of the predicted mRNA target, the methyl-CpG-binding protein (MeCP2). We also demonstrate that MeCP2 is under-expressed in DS brain specimens isolated from either humans or mice. We further demonstrate that, as a consequence of attenuated MeCP2 expression, transcriptionally activated and silenced MeCP2 target genes, CREB1/Creb1 and MEF2C/Mef2c, are also aberrantly expressed in these DS brain specimens. Finally, in vivo silencing of endogenous miR-155 or -802, by antagomir intraventricular injection, resulted in the normalization of MeCP2 and MeCP2 target gene expression. Taken together, these results suggest that improper repression of MeCP2, secondary to trisomic overexpression of Hsa21-derived miRNAs, may contribute, in part, to the abnormalities in the neurochemistry observed in the brains of DS individuals. Finally these results suggest that selective inactivation of Hsa21-derived miRNAs may provide a novel therapeutic tool in the treatment of DS.",
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AU - Nuovo, Gerard J.

AU - Terry, Alvin V

AU - Martin, Mickey M.

AU - Malana, Geraldine E.

AU - Sansom, Sarah E.

AU - Pleister, Adam P.

AU - Beck, Wayne D.

AU - Head, Elizabeth

AU - Feldman, David S.

AU - Elton, Terry S.

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AB - Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. Bioinformatic annotation has established that human chromosome 21 (Hsa21) harbors five microRNA (miRNAs) genes: miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. Our laboratory recently demonstrated that Hsa21-derived miRNAs are overexpressed in DS brain and heart specimens. The aim of this study was to identify important Hsa21-derived miRNA/mRNA target pairs that may play a role, in part, in mediating the DS phenotype.Wedemonstrate by luciferase/target mRNA 3′-untranslated region reporter assays, and gain- and loss-of-function experiments that miR-155 and -802 can regulate the expression of the predicted mRNA target, the methyl-CpG-binding protein (MeCP2). We also demonstrate that MeCP2 is under-expressed in DS brain specimens isolated from either humans or mice. We further demonstrate that, as a consequence of attenuated MeCP2 expression, transcriptionally activated and silenced MeCP2 target genes, CREB1/Creb1 and MEF2C/Mef2c, are also aberrantly expressed in these DS brain specimens. Finally, in vivo silencing of endogenous miR-155 or -802, by antagomir intraventricular injection, resulted in the normalization of MeCP2 and MeCP2 target gene expression. Taken together, these results suggest that improper repression of MeCP2, secondary to trisomic overexpression of Hsa21-derived miRNAs, may contribute, in part, to the abnormalities in the neurochemistry observed in the brains of DS individuals. Finally these results suggest that selective inactivation of Hsa21-derived miRNAs may provide a novel therapeutic tool in the treatment of DS.

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