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

doi:10.1016/j.celrep.2021.108946

MicroRNA-29 is an essential regulator of brain maturation through regulation of CH methylation

Cell Rep. 2021 Apr 6;35(1):108946. doi: 10.1016/j.celrep.2021.108946.

Authors

Vijay Swahari¹, Ayumi Nakamura², Emilie Hollville³, Hume Stroud⁴, Jeremy M Simon⁵, Travis S Ptacek⁶, Matthew V Beck³, Cornelius Flowers³, Jiami Guo³, Charlotte Plestant³, Jie Liang⁷, C Lisa Kurtz⁸, Matt Kanke⁹, Scott M Hammond¹⁰, You-Wen He⁷, E S Anton¹¹, Praveen Sethupathy¹², Sheryl S Moy¹³, Michael E Greenberg⁴, Mohanish Deshmukh¹⁴

Affiliations

¹ Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA. Electronic address: [email protected].
² Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, USA.
³ Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA.
⁴ Department of Neurobiology, Harvard University, Boston, MA, USA.
⁵ 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.
⁶ Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA.
⁷ Department of Immunology, Duke University, Durham, NC, USA.
⁸ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁹ Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.
¹⁰ Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA.
¹¹ 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.
¹² Department of Genetics, University of North Carolina, Chapel Hill, NC, USA; Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.
¹³ Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA.
¹⁴ 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. Electronic address: [email protected].

Abstract

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.

Keywords: CH methylation; DNMT3A; MeCP2; autism; epilepsy; miR-29; miRNA; neurodevelopmental disorders; non-CG methylation; seizures.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions / genetics
Animals
Animals, Newborn
Base Sequence
Behavior, Animal
Brain / growth & development*
Brain / metabolism*
DNA (Cytosine-5-)-Methyltransferases / metabolism
DNA Methylation / genetics*
Down-Regulation / genetics
Gene Expression Regulation, Developmental
Mice
Mice, Inbred C57BL
MicroRNAs / genetics
MicroRNAs / metabolism*
Neurodevelopmental Disorders / genetics
Neurodevelopmental Disorders / pathology
Neurons / metabolism
Neurons / pathology
Seizures / genetics
Seizures / pathology
Signal Transduction
Synapses / metabolism
Up-Regulation / genetics

Substances

3' Untranslated Regions
MIRN29 microRNA, mouse
MicroRNAs
DNA (Cytosine-5-)-Methyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding