Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory

Abstract

Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis-regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 (Mll1), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC. Impaired working memory after Kmt2a/Mll1 ablation in PFC neurons was associated with loss of training-induced transient waves of Arc immediate early gene expression critical for synaptic plasticity. Medial prefrontal layer V pyramidal neurons, a major output relay of the cortex, demonstrated severely impaired synaptic facilitation and temporal summation, two forms of short-term plasticity essential for working memory. Chromatin immunoprecipitation followed by deep sequencing in Mll1-deficient cortical neurons revealed downregulated expression and loss of the transcriptional mark, trimethyl-H3K4, at Ͻ50 loci, including the homeodomain transcription factor Meis2. Small RNAmediated Meis2 knockdown in PFC was associated with working memory defects similar to those elicited by Mll1 deletion. Therefore, mature prefrontal neurons critically depend on maintenance of Mll1-regulated H3K4 methylation at a subset of genes with an essential role in cognition and emotion.

Reconsolidation and extinction: Using epigenetic signatures to challenge conventional wisdom

“…Though less frequently studied, another important group of enzymes inducing PTM are histone methyltransferases (HMTs) and histone demethylases (HDMs), which add or remove a methyl group to the histone tail, respectively. Their involvement in memory consolidation has also been confirmed in several studies (Gupta-Agarwal et al, 2014; Jakovcevski et al, 2015; Snigdha et al, 2016). To date, our knowledge is limited on how the various histone modification enzymes and consequently histone modifications themselves interact with each other during memory consolidation.…”

Don't worry; be informed about the epigenetics of anxiety

“…Tri-methylation of H3K4 at this site is associated with genes transcriptionally activated. Mice bred with PFC-specific knockdown of Mll1 displayed elevated anxiety-like behaviors indicated by increased aversion to the bright compartment in the light/dark box test and reduced time spent in the center of the open field (Jakovcevski et al , 2015). A separate group of mice displayed similar anxiety levels when the Kmt1a ( Mll1 ) gene was deleted from PFC neurons in adulthood.…”

Pharmacological modulation of astrocytes and the role of cell type-specific histone modifications for the treatment of mood disorders

“…Different cell types were isolated either by using EGFP reporter mice in conjunction with flow cytometry or by binding to panning plates [37]. Similarly, purified nuclei from specific cell types can be obtained from isolation of nuclei (transgenically) tagged in specific cell types (INTACT) using antibody coated magnetic beads [39]. These sorting methods can be used for cell type specific RNAseq and ChIPseq approaches.…”

“…(a) Expression levels of deacetylases (HDACs and Sirtuins) and (b) histone acetyltransferases (HATs) and (c) histone methyl-transferases and (d) histone demethylases. (e,f) Alternative methods well suited for cell type specific ChIPseq [38,39] and RNAseq [40], respectively, are (e) fluorescence activated cellsorting (FACsorting) or (f) the use of RiboTag mice. (e) Photomicrographs show positive selection of neuronal (NeuN+) versus non-neuronal (NeuN−) cells from mouse brain after FACS.…”