Genomic landscape of human allele-specific DNA methylation

Abstract

DNA methylation mediates imprinted gene expression by passing an epigenomic state across generations and differentially marking specific regulatory regions on maternal and paternal alleles. Imprinting has been tied to the evolution of the placenta in mammals and defects of imprinting have been associated with human diseases. Although recent advances in genome sequencing have revolutionized the study of DNA methylation, existing methylome data remain largely untapped in the study of imprinting. We present a statistical model to describe allele-specific methylation (ASM) in data from high-throughput short-read bisulfite sequencing. Simulation results indicate technical specifications of existing methylome data, such as read length and coverage, are sufficient for fullgenome ASM profiling based on our model. We used our model to analyze methylomes for a diverse set of human cell types, including cultured and uncultured differentiated cells, embryonic stem cells and induced pluripotent stem cells. Regions of ASM identified most consistently across methylomes are tightly connected with known imprinted genes and precisely delineate the boundaries of several known imprinting control regions. Predicted regions of ASM common to multiple cell types frequently mark noncoding RNA promoters and represent promising starting points for targeted validation. More generally, our model provides the analytical complement to cutting-edge experimental technologies for surveying ASM in specific cell types and across species.

Q-RRBS: a quantitative reduced representation bisulfite sequencing method for single-cell methylome analyses

“…Notably, we found that one ASM region located within the promoter of ZNF718 was also common to all 9 tissues. Although conclusive experimental data are not available for characterizing ZNF718 as an imprinting gene, our findings agree with those of a statistical model developed by Fang et al., which identified ZNF718 as a candidate imprinting gene 22 . Nevertheless, our results demonstrate that Q-RRBS can be used to accurately identify ASM regions by using UMIs.…”

MethylPurify: tumor purity deconvolution and differential methylation detection from single tumor DNA methylomes

“…DNA methylation is an important epigenetic mark controlling gene expression, thus playing pivotal roles in many cellular processes including embryonic development [1], genomic imprinting [2,3], X-chromosome inactivation [4], transposable element repression [5], and preservation of chromosome stability [6]. Aberrant DNA methylations are known to be associated with human diseases such as cancers, lupus, muscular dystrophy, and imprintingrelated birth defects [7][8][9][10][11][12][13][14].…”

Single-cell epigenomics: techniques and emerging applications

“…Another open problem in the analysis of single-cell methylation data is the resolution (known as phasing) of epi-haplotypes to allow recovery of a single-chromosome methylome in diploid cells 44 . Phasing can be important for physically linking the methylation state of promoters, regulatory elements and transcribed units in cis.…”