Large-scale structure of genomic methylation patterns

Abstract

The mammalian genome depends on patterns of methylated cytosines for normal function, but the relationship between genomic methylation patterns and the underlying sequence is unclear. We have characterized the methylation landscape of the human genome by global analysis of patterns of CpG depletion and by direct sequencing of 3073 unmethylated domains and 2565 methylated domains from human brain DNA. The genome was found to consist of short (<4 kb) unmethylated domains embedded in a matrix of long methylated domains. Unmethylated domains were enriched in promoters, CpG islands, and first exons, while methylated domains comprised interspersed and tandem-repeated sequences, exons other than first exons, and non-annotated single-copy sequences that are depleted in the CpG dinucleotide. The enrichment of regulatory sequences in the relatively small unmethylated compartment suggests that cytosine methylation constrains the effective size of the genome through the selective exposure of regulatory sequences. This buffers regulatory networks against changes in total genome size and provides an explanation for the C value paradox, which concerns the wide variations in genome size that scale independently of gene number. This suggestion is compatible with the finding that cytosine methylation is universal among large-genome eukaryotes, while many eukaryotes with genome sizes <5 x 10(8) bp do not methylate their DNA.

Regulation of mammalian gene expression by retroelements and non‐coding tandem repeats

“…(63) CpG methylation increases CpG deamination in germ line cells, thus accelerating mutational inactivation of active retroelements. (21) The rate of CpG mutations in Alu is about six times higher than that the rate of non-CpG substitutions. (64) However, not only retroelements but many other sequences are methylated in genomes and mutate at higher rates because of CpG decay.…”

“…(61) In the human genome, $50% of all CpGs is associated with SINEs, LINEs and LTRs and many of them are methylated in somatic and germ line cells. (21) SINEs are excluded from imprinted regions in the human genome (62) which may be caused by their ability to silence gene expression through attraction of de novo DNA methylation. (63) CpG methylation increases CpG deamination in germ line cells, thus accelerating mutational inactivation of active retroelements.…”

“…(65) It has been suggested that DNA methylation suppresses transposable elements because it prevents the binding of transcription factors and acts to constrain the effective size of the genome by the masking of non-coding DNA. (21) However, in somatic cells, only about 60% of all CpGs is normally methylated (21,65) and a significant number of non-methylated retroelements can interact with transcription factors and effect expression of adjacent genes. In contrast, many transcription factors bind sequence motifs that do not contain CpG and their interaction with retroelements may not be suppressed by methylation.…”

“…SINEs and LINEs show clustering in gene-rich and AT-rich gene-poor genome segments, respectively. (17)(18)(19)(20) Furthermore, retroelements are heavily methylated in somatic and germ-line cells (21) and inherited epigenetic patterns of their methylation can effect expression of adjacent genes. (22,23) Since SINEs and LINEs are very abundant, they may also facilitate compartmentalization in the nucleus of transcribed and non-transcribed domains.…”

Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta

“…On the other hand, tumorigenesis is also associated with a global reduction of 5-methylcytosine content (Ehrlich, 2002). This reduction can be attributed to repetitive sequences, which make up about 45% of the human genome (Rollins et al, 2006) and are frequently hypomethylated in tumors. Low levels of DNA methylation have been found in the Alu (Weisenberger et al, 2005) and LINE-1 (Ehrlich, 2002) elements dispersed throughout the genome in cancer cells.…”