LINE-1 and Alu methylation signatures in autism spectrum disorder and their associations with the expression of autism-related genes

Abstract

Long interspersed nucleotide element-1 (LINE-1) and Alu elements are retrotransposons whose abilities cause abnormal gene expression and genomic instability. Several studies have focused on DNA methylation profiling of gene regions, but the locus-specific methylation of LINE-1 and Alu elements has not been identified in autism spectrum disorder (ASD). Here we interrogated locus- and family-specific methylation profiles of LINE-1 and Alu elements in ASD whole blood using publicly-available Illumina Infinium 450 K methylation datasets from heterogeneous ASD and ASD variants (Chromodomain Helicase DNA-binding 8 (CHD8) and 16p11.2del). Total DNA methylation of repetitive elements were notably hypomethylated exclusively in ASD with CHD8 variants. Methylation alteration in a family-specific manner including L1P, L1H, HAL, AluJ, and AluS families were observed in the heterogeneous ASD and ASD with CHD8 variants. Moreover, LINE-1 and Alu methylation within target genes is inversely related to the expression level in each ASD variant. The DNA methylation signatures of the LINE-1 and Alu elements in ASD whole blood, as well as their associations with the expression of ASD-related genes, have been identified. If confirmed in future larger studies, these findings may contribute to the identification of epigenomic biomarkers of ASD.

Investigation of autism-related transcription factors underlying sex differences in the effects of bisphenol A on transcriptome profiles and synaptogenesis in the offspring hippocampus

“…ASD is a male-biased disorder that is at least four times more common in males than in females [ 17 ]. The exact cause of ASD is still unclear, but it is thought that both genetic and environmental factors influence ASD [ 10 , 13 , 14 , 18 – 22 ]. Moreover, recent studies have reported that epigenetic regulatory mechanisms, including DNA methylation [ 19 , 20 , 22 ], histone modifications [ 23 , 24 ], and noncoding RNA-associated gene silencing [ 25 ], are associated with ASD.…”

“…The exact cause of ASD is still unclear, but it is thought that both genetic and environmental factors influence ASD [ 10 , 13 , 14 , 18 – 22 ]. Moreover, recent studies have reported that epigenetic regulatory mechanisms, including DNA methylation [ 19 , 20 , 22 ], histone modifications [ 23 , 24 ], and noncoding RNA-associated gene silencing [ 25 ], are associated with ASD. Environmental factors that are thought to cause or increase the susceptibility of ASD include BPA and bisphenol-related compounds [ 10 , 13 , 14 , 18 , 26 – 28 ], polychlorinated biphenyls (PCBs), phthalates [ 29 , 30 ], and cigarette smoke [ 31 ].…”

Epigenetic Gene-Regulatory Loci in Alu Elements Associated with Autism Susceptibility in the Prefrontal Cortex of ASD

“…These genes are known to be associated with neurodevelopmental disorders [ 20 , 21 ]. Locus- and family-specific Alu and LINE-1 methylation and the expression level of their host genes were found to be altered in the blood of ASD individuals identified using the Infinium 450 K platform [ 22 ]. Global LINE-1 methylation was significantly decreased in the blood samples from ASD individuals with mental regression [ 23 ].…”

Activation of Young LINE-1 Elements by CRISPRa

“…Most of these sequences belong to ancestral/old LINE-1 subfamilies, such as L1M (mammalian-specific, oldest), no longer mobilize, and are thought to be largely non-functional. Only a small fraction of LINE-1 sequences, including L1HS/L1PA1 (human-specific, youngest) and the young L1PA subfamilies from L1P (primate-specific, intermediate), are of full length and capable of retrotransposition [ 3 ]. A human full-length L1 transcript is 6 kb long and has a 900 nt 5′-untranslated region (UTR) that functions as a RNA polymerase II internal promoter, two open reading frames (ORF1 and ORF2), a short 3′-UTR, and a poly(A) tail.…”