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Biol Psychiatry. 2019 Jun 12. pii: S0006-3223(19)31415-5. doi: 10.1016/j.biopsych.2019.05.022. [Epub ahead of print]

The SETD6 Methyltransferase Plays an Essential Role in Hippocampus-Dependent Memory Formation.

Author information

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.

KEYWORDS:

Epigenetics; Hippocampus; Histone methylation; Memory consolidation; RELA; SETD6

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