MicroRNA-29 is an essential regulator of brain maturation through regulation of CH methylation
Vijay Swahari,
Ayumi Nakamura,
Emilie Hollville,
Hume Stroud,
Jeremy M. Simon,
Travis S. Ptacek,
Matthew V. Beck,
Cornelius Flowers,
Jiami Guo,
Charlotte Plestant,
Jie Liang,
C. Lisa Kurtz,
Matt Kanke,
Scott M. Hammond,
You-Wen He,
E.S. Anton,
Praveen Sethupathy,
Sheryl S. Moy,
Michael E. Greenberg,
Mohanish Deshmukh
Affiliations
Vijay Swahari
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Corresponding author
Ayumi Nakamura
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, USA
Emilie Hollville
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA
Hume Stroud
Department of Neurobiology, Harvard University, Boston, MA, USA
Jeremy M. Simon
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA
Travis S. Ptacek
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA
Matthew V. Beck
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA
Cornelius Flowers
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA
Jiami Guo
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA
Charlotte Plestant
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA
Jie Liang
Department of Immunology, Duke University, Durham, NC, USA
C. Lisa Kurtz
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
Matt Kanke
Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA
Scott M. Hammond
Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
You-Wen He
Department of Immunology, Duke University, Durham, NC, USA
E.S. Anton
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
Praveen Sethupathy
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA; Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA
Sheryl S. Moy
Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA
Michael E. Greenberg
Department of Neurobiology, Harvard University, Boston, MA, USA
Mohanish Deshmukh
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA; Corresponding author
Summary: Although embryonic brain development and neurodegeneration have received considerable attention, the events that govern postnatal brain maturation are less understood. Here, we identify the miR-29 family to be strikingly induced during the late stages of brain maturation. Brain maturation is associated with a transient, postnatal period of de novo non-CG (CH) DNA methylation mediated by DNMT3A. We examine whether an important function of miR-29 during brain maturation is to restrict the period of CH methylation via its targeting of Dnmt3a. Deletion of miR-29 in the brain, or knockin mutations preventing miR-29 to specifically target Dnmt3a, result in increased DNMT3A expression, higher CH methylation, and repression of genes associated with neuronal activity and neuropsychiatric disorders. These mouse models also develop neurological deficits and premature lethality. Our results identify an essential role for miR-29 in restricting CH methylation in the brain and illustrate the importance of CH methylation regulation for normal brain maturation.
