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

Academic Article


  • 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.
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    Digital Object Identifier (doi)

    Author List

  • Webb WM; Irwin AB; Pepin ME; Henderson BW; Huang V; Butler AA; Herskowitz JH; Wende AR; Cash AE; Lubin FD
  • Start Page

  • 577
  • End Page

  • 587
  • Volume

  • 87
  • Issue

  • 6