William M Webb1, Ashleigh B Irwin1, Mark E Pepin2, Benjamin W Henderson3, Victoria Huang1, Anderson A Butler1, Jeremy H Herskowitz3, Adam R Wende4, Andrew E Cash1, Farah D Lubin5. 1. Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, Alabama. 2. Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, Alabama. 3. Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama. 4. Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, Alabama; Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama. 5. Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: flubin@uab.edu.
Abstract
BACKGROUND: Epigenetic mechanisms are critical for hippocampus-dependent memory formation. Building on previous studies that implicate the N-lysine methyltransferase SETD6 in the activation of nuclear factor-κB RELA (also known as transcription factor p65) as an epigenetic recruiter, we hypothesized that SETD6 is a key player in the epigenetic control of long-term memory. METHODS: Using a series of molecular, biochemical, imaging, electrophysiological, and behavioral experiments, we interrogated the effects of short interfering RNA-mediated knockdown of Setd6 in the rat dorsal hippocampus during memory consolidation. RESULTS: Our findings demonstrate that SETD6 is necessary for memory-related nuclear factor-κB RELA methylation at lysine 310 and associated increases in H3K9me2 (histone H3 lysine 9 dimethylation) in the dorsal hippocampus and that SETD6 knockdown interferes with memory consolidation, alters gene expression patterns, and disrupts spine morphology. CONCLUSIONS: Together, these findings suggest that SETD6 plays a critical role in memory formation and may act as an upstream initiator of H3K9me2 changes in the hippocampus during memory consolidation.
BACKGROUND: Epigenetic mechanisms are critical for hippocampus-dependent memory formation. Building on previous studies that implicate the N-lysine methyltransferase SETD6 in the activation of nuclear factor-κB RELA (also known as transcription factor p65) as an epigenetic recruiter, we hypothesized that SETD6 is a key player in the epigenetic control of long-term memory. METHODS: Using a series of molecular, biochemical, imaging, electrophysiological, and behavioral experiments, we interrogated the effects of short interfering RNA-mediated knockdown of Setd6 in the rat dorsal hippocampus during memory consolidation. RESULTS: Our findings demonstrate that SETD6 is necessary for memory-related nuclear factor-κB RELA methylation at lysine 310 and associated increases in H3K9me2 (histone H3 lysine 9 dimethylation) in the dorsal hippocampus and that SETD6 knockdown interferes with memory consolidation, alters gene expression patterns, and disrupts spine morphology. CONCLUSIONS: Together, these findings suggest that SETD6 plays a critical role in memory formation and may act as an upstream initiator of H3K9me2 changes in the hippocampus during memory consolidation.
Authors: Benjamin D Boros; Kelsey M Greathouse; Erik G Gentry; Kendall A Curtis; Elizabeth L Birchall; Marla Gearing; Jeremy H Herskowitz Journal: Ann Neurol Date: 2017-10-22 Impact factor: 10.422
Authors: Yanqi Chang; Dan Levy; John R Horton; Junmin Peng; Xing Zhang; Or Gozani; Xiaodong Cheng Journal: Nucleic Acids Res Date: 2011-04-22 Impact factor: 16.971
Authors: Dan Levy; Alex J Kuo; Yanqi Chang; Uwe Schaefer; Christopher Kitson; Peggie Cheung; Alexsandra Espejo; Barry M Zee; Chih Long Liu; Stephanie Tangsombatvisit; Ruth I Tennen; Andrew Y Kuo; Song Tanjing; Regina Cheung; Katrin F Chua; Paul J Utz; Xiaobing Shi; Rab K Prinjha; Kevin Lee; Benjamin A Garcia; Mark T Bedford; Alexander Tarakhovsky; Xiaodong Cheng; Or Gozani Journal: Nat Immunol Date: 2010-12-05 Impact factor: 25.606