DNA methylation variation of human-specific Alu repeats

Abstract

DNA methylation is the major repression mechanism for human retrotransposons, such as the Alu family. Here, we have determined the methylation levels associated with 5238 loci belonging to 2 Alu subfamilies, AluYa5 and AluYb8, using high-throughput targeted repeat element bisulfite sequencing (HT-TREBS). The results indicate that »90% of loci are repressed by high methylation levels. Of the remaining loci, many of the hypomethylated elements are found near gene promoters and show high levels of DNA methylation variation. We have characterized this variation in the context of tumorigenesis and interindividual differences. Comparison of a primary breast tumor and its matched normal tissue revealed early DNA methylation changes in »1% of AluYb8 elements in response to tumorigenesis. Simultaneously, AluYa5/ Yb8 elements proximal to promoters also showed differences in methylation of up to one order of magnitude, even between normal individuals. Overall, the current study demonstrates that early loss of methylation occurs during tumorigenesis in a subset of young Alu elements, suggesting their potential clinical relevance. However, approaches such as deep-bisulfite-sequencing of individual loci using HT-TREBS are required to distinguish clinically relevant loci from the background observed for AluYa5/Yb8 elements in general with regard to high levels of interindividual variation in DNA methylation.Abbreviations: BRCA1, Breast cancer 1, early onset; BRCA2, Breast cancer 2 early onset; CEBPG, CCAAT/enhancer binding protein (C/EBP)

Perinatal lead (Pb) exposure results in sex and tissue‐dependent adult DNA methylation alterations in murine IAP transposons

“…Sex‐related differences in disease outcomes following exposure may reflect the timing of exposure relative to epigenetic programing events that occur during different developmental periods for males and females (Schneider et al, ). Furthermore, previous studies in humans have highlighted that variations in methylation, even in a small percentage of retrotransposon loci, can underlie major changes in gene expression and contribute to a disease phenotype (Bakshi et al, ).…”

“…The retrotransposon class of TEs can relocate via an RNA intermediate, and because these elements can function as alternative promoters, their transposition can elicit ectopic gene expression (Ostertag and Kazazian, ). Importantly, some recent evidence suggests that a small percentage of retrotransposons may be variably methylated and that these methylation patterns are potentially linked to disease status (Bakshi et al, ). Although the latter study was conducted in humans, because of ethical constraints, an investigation of the toxicoepigenetic effects of developmental Pb exposure on retrotransposon methylation patterns is most effectively performed in a model organism.…”

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

“…A few methods allow the individualized analysis of DNA methylation in Alu repeats at genome scale by applying massive sequencing to bisulfite and/or enzyme treated DNA (Lister et al 2009;Xie et al 2009Xie et al , 2010Edwards et al 2010;Bakshi et al 2016). These approaches offer interesting alternatives and complementary features to profile the DNA methylation landscape of Alu repeats, although they also present technical and computational constraints precluding a broad applicability.…”

An integrative review of methylation at the serotonin transporter gene and its dialogue with environmental risk factors, psychopathology and 5-HTTLPR

“…Traditionally, CpG sites located within a CpG island have been described to be hypomethylated; while CpG sites located outside CpG islands, also described as the "open sea", usually appear hypermethylated. It is widely accepted that higher methylation within a promoter-located CpG island correlates with decreased gene expression; in the same manner, higher methylation in Alu elements could prevent their expression (Bakshi et al, 2016). Notably, the transcription of Alu elements competes with transcripts close by thus diminishing their expression (Kaer and Speek, 2013).…”