Variation of global DNA methylation levels with age and in autistic children
Tsang et al. Human Genomics
Variation of global DNA methylation levels with age and in autistic children
Shui-Ying Tsang 1 2
Tanveer Ahmad 1 2
Flora W. K. Mat 2
Cunyou Zhao 2 4
Shifu Xiao 0
Kun Xia 3
Hong Xue 2
0 Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine , Shanghai 200030 , China
1 Equal contributors
2 Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology , Clear Water Bay, Hong Kong , China
3 The State Key Laboratory of Medical Genetics, Central South University , Changsha, Hunan 410078 , China
4 Department of Medical Genetics, School of Basic Medical Science, Southern Medical University , Guangzhou, Guangdong 510515 , China
Background: The change in epigenetic signatures, in particular DNA methylation, has been proposed as risk markers for various age-related diseases. However, the course of variation in methylation levels with age, the difference in methylation between genders, and methylation-disease association at the whole genome level is unclear. In the present study, genome-wide methylation levels in DNA extracted from peripheral blood for 2116 healthy Chinese in the 2-97 age range and 280 autistic trios were examined using the fluorescence polarizationbased genome-wide DNA methylation quantification method developed by us. Results: Genome-wide or global DNA methylation levels proceeded through multiple phases of variation with age, consisting of a steady increase from age 2 to 25 (r = 0.382) and another rise from age 41 to 55 to reach a peak level of ~80 % (r = 0.265), followed by a sharp decrease to ~40 % in the mid-1970s (age 56 to 75; r = −0.395) and leveling off thereafter. Significant gender effect in methylation levels was observed only for the 41-55 age group in which methylation in females was significantly higher than in males (p = 0.010). In addition, global methylation level was significantly higher in autistic children than in age-matched healthy children (p < 0.001). Conclusions: The multiphasic nature of changes in global methylation levels with age was delineated, and investigation into the factors underlying this profile will be essential to a proper understanding of the aging process. Furthermore, this first report of global hypermethylation in autistic children also illustrates the importance of agematched controls in characterization of disease-associated variations in DNA methylation.
Aging; Autism spectrum disorder; CpG methylation; Developmental epigenetics; Genome-wide methylation quantification
Background
Genetic changes can alter the genomic DNA sequence
through point mutations, insertions, deletions, copy
number variations, and chromosomal rearrangements while
epigenetic modifications can modulate phenotype and
gene expressions. DNA methylation is the most common
epigenetic modification that plays an essential role in the
regulation of tissue-specific gene expression, cellular
differentiation, chromosome stabilization, genomic imprinting,
and suppression of transposable element mobility [
1, 2
].
DNA methylation through DNA methyltransferases
convert cytosine to 5-methycytocine, with the majority of the
conversions occurring at CpG islands found in gene
promoter regions. Aberrant DNA methylation patterns have
long been associated with various human diseases
including cancers, cardiovascular diseases, psychotic disorders,
and autism [
3–6
].
Changes in epigenetics signatures, and in particular
DNA methylation, have been reported to occur in
normal physiological development and aging, and
alterations in DNA methylation associated with the signaling
and regulation of transcription have been demonstrated
in some genes [
7, 8
]. Aging is the gradual deterioration
of various body functions and represents an important
risk factor for various age-related diseases such as
cancer, neurodegenerative disorders, cardiovascular diseases,
and type 2 diabetes mellitus [9]. Several studies have
examined DNA methylation changes in old age as
disease risk factor, focusing mostly on CpG islands and
promoter regions in specific gene [
10, 11
]. However, the
characterization of lifelong age-related changes in DNA
methylation at the whole genome level has remained a
largely unexplored area.
During the past decades, various HPLC-based,
sequencing-based, (e.g., bisulfite-sequencing and
methylated DNA immunoprecipitation) and microarray-based
methods have been introduced to quantitate genomic
DNA methylation [
12
]. Although these methods enable
high-resolution and detailed methylation profiles of
individual genes, they are time-consuming and incapable of
measuring whole genome methylation levels accurately.
Recently, a number of methods have been developed to
render possible the measurement of whole genome
methylation levels, including the LUminometric Methylation
Assay (LUMA) method [
13
], the ELISA-based approach
[
14
], a (...truncated)