DNA Methylation in the Human Cerebral Cortex Is Dynamically Regulated throughout the Life Span and Involves Differentiated Neurons

Abstract

The role of DNA cytosine methylation, an epigenetic regulator of chromatin structure and function, during normal and pathological brain development and aging remains unclear. Here, we examined by MethyLight PCR the DNA methylation status at 50 loci, encompassing primarily 5′ CpG islands of genes related to CNS growth and development, in temporal neocortex of 125 subjects ranging in age from 17 weeks of gestation to 104 years old. Two psychiatric disease cohorts—defined by chronic neurodegeneration (Alzheimer's) or lack thereof (schizophrenia)—were included. A robust and progressive rise in DNA methylation levels across the lifespan was observed for 8/50 loci (GABRA2, GAD1, HOXA1, NEUROD1, NEUROD2, PGR, STK11, SYK) typically in conjunction with declining levels of the corresponding mRNAs. Another 16 loci were defined by a sharp rise in DNA methylation levels within the first few months or years after birth. Disease-associated changes were limited to 2/50 loci in the Alzheimer's cohort, which appeared to reflect an acceleration of the age-related change in normal brain. Additionally, methylation studies on sorted nuclei provided evidence for bidirectional methylation events in cortical neurons during the transition from childhood to advanced age, as reflected by significant increases at 3, and a decrease at 1 of 10 loci. Furthermore, the DNMT3a de novo DNA methyl-transferase was expressed across all ages, including a subset of neurons residing in layers III and V of the mature cortex. Therefore, DNA methylation is dynamically regulated in the human cerebral cortex throughout the lifespan, involves differentiated neurons, and affects a substantial portion of genes predominantly by an age-related increase.

Differential Promoter Methylation and Histone Modification Contribute to the Brain Specific Expression of the Mouse Mbu-1 Gene

“…In a comprehensive DNA analysis of neuronal and non-neuronal nuclei obtained from the human prefrontal cortex, neuronal nuclei manifested qualitatively and quantitatively distinctive DNA methylation patterns, including relative global hypomethylation, differential enrichment of transcription-factor binding sites, and higher methylation of genes expressed in astrocytes (Iwamoto et al, 2011). In a further study, DNA methylation was found to be dynamically regulated in the human cerebral cortex throughout the entire lifespan, involving differentiated neurons, and affecting a substantial portion of genes, increasing with age, predominantly (Siegmund et al, 2007).…”

CpG Methylation in Neurons: Message, Memory, or Mask?

“…The brain also shows variability in mCpG levels across the life span, with an observed loss of overall methylation with aging (Wilson et al, 1987) but both increases and decreases at the level of individual gene promoters (Siegmund et al, 2007). This bidirectional variability across the lifespan is a simple illustration of the independence of mCpG levels relative to the minor rates of cell-division or DNA synthesis in the post-mitotic brain.…”

“…For example, there is evidence for a robust expression in neurons and perhaps oligodendrocytes, but not in astroglia (Feng et al, 2005;Veldic et al, 2004). In the adult human post-mortem brain, both DNMT1 and DNMT3a are differentially expressed across the layers of the cortex and appear specifically in GABAergic interneurons and less so in pyramidal cells (Veldic et al, 2004Siegmund et al, 2007). In the brain, Dnmt1 is expressed from embryogenesis to adulthood.…”

“…Dnmt3b is the earliest de novo enzyme to be expressed in neural progenitor tissue during early embryogenesis, but it declines as Dnmt3a expression rises (Watanabe et al, 2006;Feng et al, 2005). The expression of Dnmt3a is observed from late embryogenesis (E10) to adulthood with a peak during the early postnatal period; its expression declines to lower but detectable levels in the adult brain (Feng et al, 2005) with a reported biphasic increase in older humans (Siegmund et al, 2007). This nonconstitutive and regulated expression is supported by the observation that DNMT1 seems more highly expressed in the 'interneurons' of the cortex (GABA interneurons in the cerebral cortex, and granular cells in the cerebellar cortex) than the 'output' neurons, that is, pyramidal or Purkinje cells respectively (Veldic et al, 2004).…”

“…Siegmund et al (2007), focusing on CpG island methylation of selected CNS-related gene promoters, report that the intensity of methylation varies during the life span. Individual promoters manifest an independent methylation chronology.…”