G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain

Shivakumar Subbanna, Madhu Shivakumar, Umapathy N Siddaramappa, Mariko Saito, Panaiyur S. Mohan, Asok Kumar, Ralph A. Nixon, Alexander Dmitriyevich Verin, Delphine Psychoyos, Balapal S. Basavarajappa

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Rodent exposure to binge-like ethanol during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces neuronal cell loss. However, the molecular mechanisms underlying these neuronal losses are still poorly understood. Here, we tested the possibility of histone methylation mediated by G9a (lysine dimethyltransferase) in regulating neuronal apoptosis in P7 mice exposed to ethanol. G9a protein expression, which is higher during embryogenesis and synaptogenic period compared to adult brain, is entirely confined to the cell nuclei in the developing brain. We found that ethanol treatment at P7, which induces apoptotic neurodegeneration in neonatal mice, enhanced G9a activity followed by increased histone H3 lysine 9 (H3K9me2) and 27 (H3K27me2) dimethylation. In addition, it appears that increased dimethylation of H3K9 makes it susceptible to proteolytic degradation by caspase-3 in conditions in which ethanol induces neurodegeneration. Further, pharmacological inhibition of G9a activity prior to ethanol treatment at P7 normalized H3K9me2, H3K27me2 and total H3 proteins to basal levels and prevented neurodegeneration in neonatal mice. Together, these data demonstrate that G9a mediated histone H3K9 and K27 dimethylation critically regulates ethanol-induced neurodegeneration in the developing brain. Furthermore, these findings reveal a novel link between G9a and neurodegeneration in the developing brain exposed to postnatal ethanol and may have a role in fetal alcohol spectrum disorders.

Original languageEnglish (US)
Pages (from-to)475-485
Number of pages11
JournalNeurobiology of Disease
Volume54
DOIs
StatePublished - Jun 1 2013

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Histones
Methylation
Ethanol
Brain
Lysine
Fetal Alcohol Spectrum Disorders
Third Pregnancy Trimester
Cell Nucleus
Caspase 3
Embryonic Development
Rodentia
Proteins
Pharmacology
Apoptosis

Keywords

  • Bix
  • Developing brain
  • Fetal alcohol syndrome
  • Methyltransferase
  • Neuronal loss

ASJC Scopus subject areas

  • Neurology

Cite this

G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain. / Subbanna, Shivakumar; Shivakumar, Madhu; Siddaramappa, Umapathy N; Saito, Mariko; Mohan, Panaiyur S.; Kumar, Asok; Nixon, Ralph A.; Verin, Alexander Dmitriyevich; Psychoyos, Delphine; Basavarajappa, Balapal S.

In: Neurobiology of Disease, Vol. 54, 01.06.2013, p. 475-485.

Research output: Contribution to journalArticle

Subbanna, S, Shivakumar, M, Siddaramappa, UN, Saito, M, Mohan, PS, Kumar, A, Nixon, RA, Verin, AD, Psychoyos, D & Basavarajappa, BS 2013, 'G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain', Neurobiology of Disease, vol. 54, pp. 475-485. https://doi.org/10.1016/j.nbd.2013.01.022
Subbanna, Shivakumar ; Shivakumar, Madhu ; Siddaramappa, Umapathy N ; Saito, Mariko ; Mohan, Panaiyur S. ; Kumar, Asok ; Nixon, Ralph A. ; Verin, Alexander Dmitriyevich ; Psychoyos, Delphine ; Basavarajappa, Balapal S. / G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain. In: Neurobiology of Disease. 2013 ; Vol. 54. pp. 475-485.
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