Histone H3 lysine K4 methylation and its role in learning and memory

Abstract

Epigenetic modifications such as histone methylation permit change in chromatin structure without accompanying change in the underlying genomic sequence. A number of studies in animal models have shown that dysregulation of various components of the epigenetic machinery causes cognitive deficits at the behavioral level, suggesting that proper epigenetic control is necessary for the fundamental processes of learning and memory. Histone H3 lysine K4 (H3K4) methylation comprises one component of such epigenetic control, and global levels of this mark are increased in the hippocampus during memory formation. Modifiers of H3K4 methylation are needed for memory formation, shown through animal studies, and many of the same modifiers are mutated in human cognitive diseases. Indeed, all of the known H3K4 methyltransferases and four of the known six H3K4 demethylases have been associated with impaired cognition in a neurologic or psychiatric disorder. Cognitive impairment in such patients often manifests as intellectual disability, consistent with a role for H3K4 methylation in learning and memory. As a modification quintessentially, but not exclusively, associated with transcriptional activity, H3K4 methylation provides unique insights into the regulatory complexity of writing, reading, and erasing chromatin marks within an activated neuron. The following review will discuss H3K4 methylation and connect it to transcriptional events required for learning and memory within the developed nervous system. This will include an initial discussion of the most recent advances in the developing methodology to analyze H3K4 methylation, namely mass spectrometry and deep sequencing, as well as how these methods can be applied to more deeply understand the biology of this mark in the brain. We will then introduce the core enzymatic machinery mediating addition and removal of H3K4 methylation marks and the resulting epigenetic signatures of these marks throughout the neuronal genome. We next foray into the brain, discussing changes in H3K4 methylation marks within the hippocampus during memory formation and retrieval, as well as the behavioral correlates of H3K4 methyltransferase deficiency in this region. Finally, we discuss the human cognitive diseases connected to each H3K4 methylation modulator and summarize advances in developing drugs to target them.

Keywords: Epigenetics; H3K4; Histone methylation; Learning; Memory; Neuroepigenetics.

Fig. 1

Cognitive diseases associated with dysregulation of H3K4 methylation. Associated diseases fall under three different DSM-5 groupings: Neurodevelopmental disorders, schizophrenia spectrum and other psychotic disorders, and substance-related and addictive disorders. Neurodevelopmental disorders encompass both ID and ASD. Beneath each DSM-5 disorder is an icon that either symbolizes the disorder or depicts a key clinical feature of it (Far left: A collection of puzzle pieces, representing the complexity of genetic and non-genetic etiologies of ID. Middle left: A blue puzzle piece, one of the symbols of ASD used by advocacy organizations. Middle right: A representation of visual and auditory hallucinations experienced by patients with schizophrenia. Far right: A prescription bottle of hydrocodone, representing one of the compounds used by patients with this disorder)

Fig. 2

H3K4 methylation marks and their genomic distributions. a Histone octamers, comprised of two of each histone H2A, H2B, H3, and H4 subunits, are wrapped by DNA to form nucleosomes. An N-terminal tail protrudes from each histone subunit, containing residues amenable to posttranslational modification. Lysine residue K4 on H3 can be mono- (orange), di- (green), or tri- (blue) methylated, forming H3K4me1, H3K4me2, or H3K4me3, respectively. b H3K4me1, H3K4me2, and H3K4me3 are located in different regions throughout the genome. H3K4me3, H3K4me2, and H3K4me1 are found in increasingly broad distributions about the TSSs of actively transcribed genes. Additionally, H3K4me1 is found at distal regions acting as enhancers

Fig. 3

Enzymology of H3K4 methylation and demethylation. a Evolutionary tree diagram of H3K4 methyltransferases from yeast (S. cerevisiae) to flies (D. melanogaster) to humans (H. sapiens). b Diagram of H3K4 methylation and demethylation reaction pathways. Mono-, di-, and trimethylation reactions are carried out by all members of the KMT2 family. H3K4me1 and H3K4me2 demethylation reactions are carried out by KDM1 and KDM5 family members. The H3K4me3 demethylation reaction is carried out by KDM5 family members. c Bubble diagram of COMPASS-like complexes formed with each KMT2 family member. Methyltransferase subunits (gray) associate with a core WRAD complex comprised of WDR5, RBP5, ASH2L, and DPY-30 (blue). Additional subunits (green) associate with specific COMPASS-like complexes to influence target selection. d Table of H3K4 methyltransferase/demethylase enzymes and alternative names used in the literature

Fig. 4

Intensity and breadth are distinct attributes of H3K4me3 peaks. H3K4me3 peaks are typically found upstream and downstream of the TSSs of active genes (TTS = transcription termination site). Peak intensity describes the level of H3K4me3 enrichment normalized to peak width. Peak breadth describes the width of H3K4me3 enrichment

Fig. 5

H3K4 methylation changes during CFC. In the CFC paradigm, naive mice are subjected to either a novel context (Context) or this novel context and an electric foot shock (Context–Shock) to precipitate formation of contextual and associative memories, respectively. Gupta et al. [5] dissected out the CA1 region of the hippocampus from these mice and subjected the tissues to ChIP-qPCR using primers to the promoters of learning genes. Increases in H3K4me3 intensity levels were observed at Bdnf and Zif268 promoters in Context–Shock mice. However, it is currently unknown whether or not H3K4me3 breadth undergoes similar changes at learning-related genes in this paradigm