title: G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain.
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.
authors: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
authors: Shivakumar
authors: S
authors: Subbanna
authors: Madhu
authors: M
authors: Shivakumar
authors: Nagavedi S
authors: NS
authors: Umapathy
authors: Mariko
authors: M
authors: Saito
authors: Panaiyur S
authors: PS
authors: Mohan
authors: Asok
authors: A
authors: Kumar
authors: Ralph A
authors: RA
authors: Nixon
authors: Alexander D
authors: AD
authors: Verin
authors: Delphine
authors: D
authors: Psychoyos
authors: Balapal S
authors: BS
authors: Basavarajappa
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D002492:Central Nervous System Depressants / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D007150:Immunohistochemistry; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000201:enzymology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002492:Central Nervous System Depressants; D006657:Histones; D000431:Ethanol; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase
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