title: Neurotrophin-mediated degradation of histone methyltransferase by S-nitrosylation cascade regulates neuronal differentiation.
abstract: Epigenetic regulation of histones mediates neurotrophin actions with histone acetylation enhancing cAMP response element-binding (CREB)-associated transcription elicited by brain-derived neurotrophic factor (BDNF) and nerve-growth factor (NGF). Roles for histone methylation in CREB's transcriptional activity have not been well characterized. We show that depletion of the histone methyltransferase suppressor of variegation 3-9 homolog 1 (SUV39H1) selectively augments BDNF- and NGF-mediated neurite outgrowth. SUV39H1 is the principal enzyme responsible for trimethylation of histone H3 at lysine 9, a molecular mark associated with transcriptional silencing. BDNF and NGF act via a signaling cascade wherein degradation of SUV39H1 down-regulates trimethylation of H3K9 in a nitric oxide-dependent pathway. BDNF activates neuronal NOS with the nitrosylated GAPDH/seven in absentia (Siah) homolog complex translocating to the nucleus. Degradation of SUV39H1 by Siah facilitates histone H3 on lysine 9 acetylation, CREB binding to DNA, enhanced expression of CREB-regulated genes and neurite outgrowth.
authors: The Solomon H Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Nilkantha
authors: N
authors: Sen
authors: Solomon H
authors: SH
authors: Snyder
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D015538:Nitrosation / Q000187:drug effects; D016716:PC12 Cells; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D051381:Rats; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D006657:Histones; D009414:Nerve Growth Factors; D009569:Nitric Oxide; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase