The emerging field of epigenetics in neurodegeneration and neuroprotection

Abstract

Epigenetic mechanisms - including DNA methylation, histone post-translational modifications and changes in nucleosome positioning - regulate gene expression, cellular differentiation and development in almost all tissues, including the brain. In adulthood, changes in the epigenome are crucial for higher cognitive functions such as learning and memory. Striking new evidence implicates the dysregulation of epigenetic mechanisms in neurodegenerative disorders and diseases. Although these disorders differ in their underlying causes and pathophysiologies, many involve the dysregulation of restrictive element 1-silencing transcription factor (REST), which acts via epigenetic mechanisms to regulate gene expression. Although not somatically heritable, epigenetic modifications in neurons are dynamic and reversible, which makes them good targets for therapeutic intervention.

Figure 1 |. Polycomb proteins in epigenetic remodelling and neuroprotection.

Ischaemic preconditioning is a well-known phenomenon in which a brief, sublethal ischaemic insult confers hippocampal CA1 neurons with robust protection against a subsequent severe ischaemic challenge^–. Ischaemic preconditioning promotes the expression of the Polycomb proteins SCMH1, BMI1 and RING2, and the core histone protein H2A, as well as the formation of Polycomb protein complex 1 (PRC1) and PRC2. PRC2 associates with the promoters of target genes. The catalytically active subunits of PRC2, enhancer of zeste homologue 1 (EZH1) and EZH2, catalyse the trimethylation of histone H3 at lysine 27 (H3K27me3), a hallmark of EZH2-mediated gene repression. Chromodomain- containing protein (CBX; also known as chromobox protein homologue 1), a component of PRC1, recognizes and binds to H3K27me3, and thereby recruits PRC1 to the promoter. SCMH1 is a component of PRC1 (REF 126) and is crucial for the neuroprotection induced by ischaemic preconditioning. The PRC1 protein BMI1 is a Polycomb ring-finger protein that protects against stress-induced cell death and p53-mediated cell death. RING2 catalyses the mono-ubiquitylation of histone H2A at lysine 119 (H2AK119ub1), a post-translational modification that represses transcript elongation by RNA polymerase. It has been shown that ischaemic preconditioning is associated with the appearance of these epigenetic marks in the promoters of the genes Kcna5 and Kcnab2 (which encode voltage-gated potassium channel subfamily A member 5 and voltage-gated potassium channel subunit β2, respectively). The presence of these marks represses Kcna5 and Kcnab2 expression, and thereby attenuates the activity of voltage-gated potassium channels in the ischaemia-tolerant brain, resulting in neuroprotection. PHC1, polyhomeotic-like protein 1; RPAP, RNA polymerase-associated protein.

Figure 2 |. Restrictive element 1-silencing transcription factor in neurodegenerativo disease.

a | In -the healthy aged brain, stress increases WNT-β-catenin signalling (specifically that mediated by WNT3A and WNT7A) in the hippocampus and the frontal cortex. This promotes the nuclear translocation of restrictive element 1-silencing transcription factor (REST) and increased binding of REST to the restrictive element 1 (RE1) sites of REST target genes. This induction of REST nuclear abundance promotes neuroprotection by repressing the transcription of genes that encode proteins involved in neuronal death (such as BCL-2-binding component 3 (BBC3), BAX, death domain-associated protein 6 (DAXX), tumour necrosis factor receptor type 1-associated death domain protein (TRADD) and BCL-2-like protein 11 (BCL2L11)) and genes that encode proteins involved in Alzheimer disease (AD) pathology (such as members of the γ-secretase complex, which is implicated in amyloid-β (Aβ) generation). In AD-affected brains, oxidative stress activates autophagy. The autophagosomes that are generated engulf REST, together with misfolded proteins such as Aβ and tau, which reduces REST abundance in the nucleus. The loss of REST in the nucleus causes an increase in expression of genes that are involved in oxidative stress and neuronal death. b | In the striatal neurons of wild-type (WT) mice, huntingtin (HTT) binds to and sequesters REST in the cytoplasm away from target genes that are important for neuronal activity and survival, such as brain-derived neurotrophic factor (BDNF)^,,. In the striatal neurons of mice carrying Huntington disease (HD)-related mutations, mutant HTT (mHTT) is unable to bind to and sequester REST, enabling REST to translocate to the nucleus where it silences target genes, thus promoting neuronal death^,. A recent study suggests that this mechanism may not apply to neurons, but rather to glial cells, in the striata of humans with HD. CoREST, REST co-repressor; H3K9ac, histone H3 lysine 9 acetylation; HDAC, histone deacetylase.