A genome-wide screen in human embryonic stem cells reveals novel sites of allele-specific histone modification associated with known disease loci

Using a statistically rigorous protocol, we investigated the genomic distribution of ASHM in hESCs, and their relationship to sites of allele-specific expression (ASE) and DNA methylation. We found that, although they were rare, sites of ASHM were substantially enriched at loci displaying ASE. Many were also found at known imprinted regions, hence sites of ASHM are likely to be better markers of imprinted regions than sites of ASM. We also found that sites of ASHM and ASE in hESCs colocalize at risk loci for developmental syndromes mediated by deletions, providing insights into the etiology of these disorders.These results demonstrate the potential importance of ASHM patterns in the interpretation of disease loci, and the protocol described provides a basis for similar studies of ASHM in other cell types to further our understanding of human disease susceptibility.In genome-wide studies of human chromatin, chromatin states are often assumed to be the same on both copies of a chromosome. However, an increasing number of studies has shown that a surprising level of heterogeneity can in fact exist between the chromatin states of different alleles. A recent study of allele-specific methylation (ASM) of DNA in various pluripotent and adult cell lines estimated that 23 to 37% of heterozygous single-nucleotide polymorphisms (SNPs) displayed differing levels of methylation between alleles, with most ASM sites attributable to heterozygote polymorphisms disrupting the guanine nucleotide in CpG motifs [1].Although DNA methylation is the best-characterized mechanism [2], it is not the only level of chromatin that has been shown to exhibit genome-wide allele-specific patterns in humans. For example, the nuclease DNaseI has been shown to cleave at sites of open chromatin and to preferentially target regulatory elements such as promoters and enhancers. Investigation of allele-specific patterns of DNaseI hypersensitivity has shown that 7% of DNaseI sites display allelic imbalances