Table 5.3.

Emerging nonmutually exclusive paradigms linking epigenetic factors and mechanisms with neurologic and psychiatric disorders

Paradigms	Examples
Mutations in genes encoding epigenetic factors are causally linked to disease pathogenesis	• Rett syndrome is caused by mutations in the methyl-CpG-binding domain protein 2 gene (Amir et al., 1999) • Autosomal-dominant cerebellar ataxia, deafness, and narcolepsy syndrome (Winkelmann et al., 2012) and hereditary sensory neuropathy type IE (Klein et al., 2011) are caused by mutations in the DNA methyltransferase 1 gene • Intellectual and developmental disability syndromes are caused by mutations in an increasing array of histone modification and chromatin-remodeling genes (e.g., histone lysine-specific demethylase 5C and 6A and alpha thalassemia/mental retardation syndrome X-linked) (Kleefstra et al., 2014) and the LINC00299 gene (Talkowski et al., 2012) • Progressive encephalopathy with severe infantile anorexia (Ravine encephalopathy) is caused by a mutation in the SLC7A2-IT1 long noncoding RNA (lncRNA) gene (Cartault et al., 2012) • Pediatric gliomas are linked to somatic mutations in the histone H3 gene (Schwartzentruber et al., 2012; Wu et al., 2012) • Medulloblastomas are associated with somatic mutations in histone lysine methylation-related factors (Northcott et al., 2009; Parsons et al., 2011; Pugh et al., 2012)
Variations in genes encoding epigenetic factors are implicated in modifying disease onset and progression	• Major depressive disorder with susceptibility to chronobiologic subphenotypes (insomnia) is associated with a single-nucleotide polymorphism (SNP) in the miR-182 microRNA (miRNA) gene (Saus et al., 2010) • Large-vessel ischemic stroke risk is modified by an SNP in the histone deacetylase 9 (HDAC9) gene (Bellenguez et al., 2012) • Juvenile myoclonic epilepsy susceptibility is modified by SNPs in the bromodomain-containing protein 2 gene (Pal et al., 2003)
Impairments in epigenetic factor expression, localization, or function are involved in disease mechanisms	• RE1-silencing transcription factor is aberrantly sequestered in the nucleus and its activity deregulated in Huntington disease (Zuccato et al., 2003; Buckley et al., 2010) • HDAC4 accumulates in the nucleus and its activity is deregulated in ataxia telangiectasia, leading to neurodegeneration (Li et al., 2012) • Deregulation of adenosine deaminase 2 is implicated in AMPA receptor-mediated death of motor neurons in amyotrophic lateral sclerosis (Hideyama et al., 2010, 2012) and vulnerability of neurons to ischemia (Peng et al., 2006)
Epigenetic regulatory mechanisms are responsible for modulating disease-associated genomic loci, gene products, and pathways	• Prader–Willi and Angelman syndromes are caused by genomic imprinting defects on chromosome 15q11–13 (Buiting, 2010) • BACE1 antisense RNA is an lncRNA transcribed antisense to the β-site APP-cleaving enzyme 1 (BACE1) gene, which is implicated in Alzheimer disease (AD) and responsible for regulating the BACE1 mRNA (Faghihi et al., 2008) • miR-339–5p is a miRNA that also modulates BACE1 and is deregulated in AD (Long et al., 2014)
Epigenetic profiles are deregulated in patient-derived central and peripheral tissues	• Differential DNA methylation of the transient receptor potential cation channel, subfamily A, member 1 gene promoter in blood from identical twin pairs is robustly associated with sensitivity to pain (Bell et al., 2014) • Differential DNA methylation at multiple genomic sites, encompassing known AD susceptibility loci, in human brain specimens is linked to AD onset and progression and neuropathologic hallmarks (De Jager et al., 2014; Lunnon et al., 2014; Yu et al., 2015) • Differential DNA methylation is present at multiple genomic sites in pathology-free brain regions derived from multiple sclerosis patients (Huynh et al., 2014) • Differential DNA methylation is present in blood from patients with neurodegenerative taupoathies (progressive supranuclear palsy (PSP) and frontotemporal dementia) (Li et al., 2014). For PSP, these patterns are clustered within the known susceptibility locus on 17q21.31