Neuroepigenetic mechanisms in disease

Abstract

Epigenetics allows for the inheritance of information in cellular lineages during differentiation, independent of changes to the underlying genetic sequence. This raises the question of whether epigenetic mechanisms also function in post-mitotic neurons. During the long life of the neuron, fluctuations in gene expression allow the cell to pass through stages of differentiation, modulate synaptic activity in response to environmental cues, and fortify the cell through age-related neuroprotective pathways. Emerging evidence suggests that epigenetic mechanisms such as DNA methylation and histone modification permit these dynamic changes in gene expression throughout the life of a neuron. Accordingly, recent studies have revealed the vital importance of epigenetic players in the central nervous system and during neurodegeneration. Here, we provide a review of several of these recent findings, highlighting novel functions for epigenetics in the fields of Rett syndrome, Fragile X syndrome, and Alzheimer's disease research. Together, these discoveries underscore the vital importance of epigenetics in human neurological disorders.

Keywords: Alzheimer’s disease; DNA methylation; FMR1; Fragile X syndrome; Histone modification; LSD1/KDM1A; MECP2; Neuroepigenetics; Rett syndrome.

Fig. 1

Chromatin modifications and their associated factors. Transcriptionally permissive chromatin is associated with the absence of DNA methylation (open lollipops) and the presence of H3K4me3/2/1. This mark is established by the MLL and SET family of enzymes and is found in genes actively undergoing transcription. H3K4me3 is found in the promoters, H3K4me2 is found in gene bodies, and H3K4me1 is found in the enhancers of active genes. These marks are erased by demethylases such as LSD1, JARID1, and JARID1b. Transcriptionally repressive chromatin features concurrent cytosine methylation (closed lollipops) and H3K9me3. Cytosine methylation is established by the DNA methyltransferases and erased by the TET family of enzymes. H3K9me3 is established by G9a, SUV39H1, and SETDB1 and erased by JHDM2A. Alternatively, transcriptionally repressive chromatin can contain H3K27me3 and no cytosine methylation (open lollipops). H3K27me3 is established by EZH2, part of the polycomb repressive complex, and is erased by JMJD3 and UTX

Fig. 2

MeCP2 regulates long gene expression in a 5mCA-dependent manner. The 5mCG mark is commonly found enriched at gene promotor regions, while the 5mCA mark is enriched in the gene bodies of exceptionally long genes (>100 kb) in neurons. The epigenetic “reader” MeCP2 binds both marks, but has a strong affinity for 5mCA in long gene bodies. In wild-type neurons, this interaction represses transcription of long genes and may allow for fine tuning of gene expression. Currently, the machinery and mechanism by which MeCP2 silences long genes is unknown. In the Mecp2 null neuron, 5mCA marks in long genes go unrecognized and the locus is aberrantly transcribed

Fig. 3

Expanded FMR1 mRNA silences the FMR1 locus through an epigenetic mechanism. The FMR1 locus features a CGG trinucleotide repeat in the 5′UTR of the gene. Typically, the trinucleotide is repeated 5–40 times; however, expansion of this site to >200 repeats causes Fragile X syndrome. The trinucleotide repeat in the resulting expanded FMR1 mRNA transcript (1) binds to its CGG expansion at the DNA locus to form a heteroduplex. Through an unknown mechanism, this interaction silences transcription from the FMR1 locus (2). The locus then acquires a repressive chromatin state. Specifically, active histone marks H3K9ac and H3K4me2 are removed, while repressive mCG and H3K9me2 marks are added (3)

Fig. 4

LSD1 is indispensable for neuronal health. a Loss of the neuronal-specific LSD1 isoform (LSD1n) reduces neurite length, branching, and width. LSD1n-specific null neurons are also hypoexcitable, and mice have a decreased susceptibility to seizures. Alternatively, loss of the entire LSD1 transcript in adult mice causes severe, rapid neurodegeneration as demonstrated by loss of neurites and pyknosis of affected nuclei. Cell death primarily occurs in the hippocampus and cortex. LSD1 mutant mice develop learning and memory deficits and die within 8 weeks post-deletion. b A model for LSD1 in Alzheimer’s disease emerges. As pathological hyperphosphorylated Tau tangles form in aging or sick neurons, LSD1 protein is sequestered in the cytoplasm, which inhibits its function as a histone demethylase. In the absence of nuclear LSD1, the complement cascade, microglial inflammatory response, and pluripotency-associated stem pathways become upregulated, while genes associated with ion transport and oxidative phosphorylation (OXPHOS) are downregulated. Though it is currently unclear which pathways are directly detrimental to cell health and which become perturbed as secondary effects, these aberrations cause neurons to die, leading to dementia in patients