Genome-wide quantitative assessment of variation in DNA methylation patterns

Abstract

Genomic DNA methylation contributes substantively to transcriptional regulations that underlie mammalian development and cellular differentiation. Much effort has been made to decipher the molecular mechanisms governing the establishment and maintenance of DNA methylation patterns. However, little is known about genome-wide variation of DNA methylation patterns. In this study, we introduced the concept of methylation entropy, a measure of the randomness of DNA methylation patterns in a cell population, and exploited it to assess the variability in DNA methylation patterns of Alu repeats and promoters. A few interesting observations were made: (i) within a cell population, methylation entropy varies among genomic loci; (ii) among cell populations, the methylation entropies of most genomic loci remain constant; (iii) compared to normal tissue controls, some tumors exhibit greater methylation entropies; (iv) Alu elements with high methylation entropy are associated with high GC content but depletion of CpG dinucleotides and (v) Alu elements in the intronic regions or far from CpG islands are associated with low methylation entropy. We further identified 12 putative allelic-specific methylated genomic loci, including four Alu elements and eight promoters. Lastly, using subcloned normal fibroblast cells, we demonstrated the highly variable methylation patterns are resulted from low fidelity of DNA methylation inheritance.

Individual variation and longitudinal pattern of genome-wide DNA methylation from birth to the first two years of life

“…Similar conclusions apply to gene regions close to TSS vs. those further away from TSS. Consistent with a recent study on DNA methylation entropy, 38 our results indicated that methylation variation could be loci-specific and associated with the functional aspects of the corresponding genomic sequences. Higher inter-individual variations in the CpG shores and shelves and in TSS1500 indicated that these features were possibly more likely to be influenced by environmental factor exposure in utero and during early life, and thus could be strong candidates for disease differential methylation regions (DMR).…”

DNA methylation profiling in human B cells reveals immune regulatory elements and epigenetic plasticity at Alu elements during B-cell activation

“…Further, the pattern of methylation loss at Alu elements is suggestive of an alteration in nucleosome positioning at the 59 and 39 ends of these elements, consistent with a global alteration in chromatin architecture. It is also conceivable that the DNA methylation changes observed here reflect a shift from homogenous to heterogeneous methylation patterning as previously described (Xie et al 2011).…”

The dynamics of DNA methylation fidelity during mouse embryonic stem cell self-renewal and differentiation

“…The percentage of hemi-methylated CpG dyads varies considerably among these genomic segments and different cell types. On a genome-wide scale, extremely high fidelity on DNA methylation transmission was found for ;30% of genomic segments derived from CGIs and 10% of segments from Alu repeats, whereas only a small subset of CGIs and Alu elements have highly variable methylation patterns (Xie et al 2011). Notably, the methylation fidelities of CGIs and repetitive elements decrease in tumor tissues (Ushijima et al 2005;Watanabe et al 2006;Xie et al 2011).…”

“…On a genome-wide scale, extremely high fidelity on DNA methylation transmission was found for ;30% of genomic segments derived from CGIs and 10% of segments from Alu repeats, whereas only a small subset of CGIs and Alu elements have highly variable methylation patterns (Xie et al 2011). Notably, the methylation fidelities of CGIs and repetitive elements decrease in tumor tissues (Ushijima et al 2005;Watanabe et al 2006;Xie et al 2011). Epigenetic instability in embryonic stem cells has also been well documented (Humpherys et al 2001;Minoguchi and Iba 2008).…”