title: 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.
authors: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Kimberly D
authors: KD
authors: Siegmund
authors: Caroline M
authors: CM
authors: Connor
authors: Mihaela
authors: M
authors: Campan
authors: Tiffany I
authors: TI
authors: Long
authors: Daniel J
authors: DJ
authors: Weisenberger
authors: Detlev
authors: D
authors: Biniszkiewicz
authors: Rudolf
authors: R
authors: Jaenisch
authors: Peter W
authors: PW
authors: Laird
authors: Schahram
authors: S
authors: Akbarian
mesh_terms: D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D015331:Cohort Studies; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D006801:Humans; D009474:Neurons / Q000166:cytology*; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology
chemical_list: C000717967:DNMT3A protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A