TY - JOUR
T1 - G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain
AU - Subbanna, Shivakumar
AU - Shivakumar, Madhu
AU - Umapathy, Nagavedi S.
AU - Saito, Mariko
AU - Mohan, Panaiyur S.
AU - Kumar, Asok
AU - Nixon, Ralph A.
AU - Verin, Alexander D.
AU - Psychoyos, Delphine
AU - Basavarajappa, Balapal S.
N1 - Funding Information:
This work was supported by NIH/NIAAA grants AA11031 and AA019443 (BSB). Mariko Saito was supported by NIAAA grant AA015355 and Delphine Psychoyos was supported by NIDA award 5F32DA21977 .
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
KW - Bix
KW - Developing brain
KW - Fetal alcohol syndrome
KW - Methyltransferase
KW - Neuronal loss
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U2 - 10.1016/j.nbd.2013.01.022
DO - 10.1016/j.nbd.2013.01.022
M3 - Article
C2 - 23396011
AN - SCOPUS:84876311934
SN - 0969-9961
VL - 54
SP - 475
EP - 485
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -