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

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

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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.

Original language	English (US)
Article number	108946
Journal	Cell Reports
Volume	35
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2021.108946
State	Published - Apr 6 2021
Externally published	Yes

Keywords

CH methylation
DNMT3A
MeCP2
autism
epilepsy
miR-29
miRNA
neurodevelopmental disorders
non-CG methylation
seizures

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2021.108946

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Swahari, V., Nakamura, A., Hollville, E., Stroud, H., Simon, J. M., Ptacek, T. S., Beck, M. V., Flowers, C., Guo, J., Plestant, C., Liang, J., Kurtz, C. L., Kanke, M., Hammond, S. M., He, Y. W., Anton, E. S., Sethupathy, P., Moy, S. S., Greenberg, M. E., & Deshmukh, M. (2021). MicroRNA-29 is an essential regulator of brain maturation through regulation of CH methylation. Cell Reports, 35(1), Article 108946. https://doi.org/10.1016/j.celrep.2021.108946

Swahari, V, Nakamura, A, Hollville, E, Stroud, H, Simon, JM, Ptacek, TS, Beck, MV, Flowers, C, Guo, J, Plestant, C, Liang, J, Kurtz, CL, Kanke, M, Hammond, SM, He, YW, Anton, ES, Sethupathy, P, Moy, SS, Greenberg, ME & Deshmukh, M 2021, 'MicroRNA-29 is an essential regulator of brain maturation through regulation of CH methylation', Cell Reports, vol. 35, no. 1, 108946. https://doi.org/10.1016/j.celrep.2021.108946

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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.",

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author = "Vijay Swahari and Ayumi Nakamura and Emilie Hollville and Hume Stroud and Simon, {Jeremy M.} and Ptacek, {Travis S.} and Beck, {Matthew V.} and Cornelius Flowers and Jiami Guo and Charlotte Plestant and Jie Liang and Kurtz, {C. Lisa} and Matt Kanke and Hammond, {Scott M.} and He, {You Wen} and Anton, {E. S.} and Praveen Sethupathy and Moy, {Sheryl S.} and Greenberg, {Michael E.} and Mohanish Deshmukh",

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AU - Stroud, Hume

AU - Simon, Jeremy M.

AU - Ptacek, Travis S.

AU - Beck, Matthew V.

AU - Flowers, Cornelius

AU - Guo, Jiami

AU - Plestant, Charlotte

AU - Liang, Jie

AU - Kurtz, C. Lisa

AU - Kanke, Matt

AU - Hammond, Scott M.

AU - He, You Wen

AU - Anton, E. S.

AU - Sethupathy, Praveen

AU - Moy, Sheryl S.

AU - Greenberg, Michael E.

AU - Deshmukh, Mohanish

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N2 - 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.

AB - 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.

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KW - seizures

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

Abstract

Keywords

ASJC Scopus subject areas

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