Neurotrophin-mediated degradation of histone methyltransferase by S-nitrosylation cascade regulates neuronal differentiation

Nilkantha Sen, Solomon H. Snyder

Research output: Contribution to journalArticle

52 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)20178-20183
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number50
DOIs
StatePublished - Dec 13 2011

Keywords

  • Epigenetics
  • GAPDH

ASJC Scopus subject areas

  • General

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