Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p

  1. Huda Y. Zoghbi1,2,3,4,10,11,16
  1. 1Department of Molecular and Human Genetics,
  2. 2The Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA;
  3. 3The Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA;
  4. 4Department of Pediatrics, Computational and Integrative Biomedical Research Center, Baylor College of Medicine, Houston, Texas 77030, USA;
  5. 5Department of Neurobiology,
  6. 6Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA;
  7. 7Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada;
  8. 8Department of Neurology, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, California 94143, USA;
  9. 9Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
  10. 10Department of Neuroscience,
  11. 11Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

    1. ↵12 These authors contributed equally to this work.

    • ↵Present addresses: 13Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea;

    • ↵14 Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA;

    • ↵15 Department of Pediatrics, Pharmacology, and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.

    Abstract

    Proper neurological function in humans requires precise control of levels of the epigenetic regulator methyl CpG-binding protein 2 (MeCP2). MeCP2 protein levels are low in fetal brains, where the predominant MECP2 transcripts have an unusually long 3′ untranslated region (UTR). Here, we show that miR-483-5p, an intragenic microRNA of the imprinted IGF2, regulates MeCP2 levels through a human-specific binding site in the MECP2 long 3′ UTR. We demonstrate the inverse correlation of miR-483-5p and MeCP2 levels in developing human brains and fibroblasts from Beckwith-Wiedemann syndrome patients. Importantly, expression of miR-483-5p rescues abnormal dendritic spine phenotype of neurons overexpressing human MeCP2. In addition, miR-483-5p modulates the levels of proteins of the MeCP2-interacting corepressor complexes, including HDAC4 and TBL1X. These data provide insight into the role of miR-483-5p in regulating the levels of MeCP2 and interacting proteins during human fetal development.

    Keywords

    Footnotes

    • Received October 3, 2012.
    • Accepted January 28, 2013.
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    1. Published in Advance February 21, 2013, doi: 10.1101/gad.207456.112 Genes & Dev. 27: 485-490 Copyright © 2013 by Cold Spring Harbor Laboratory Press

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