Researchers have developed the first comprehensive atlas of allele-specific DNA methylation across 39 human cell types, revealing a complex landscape of epigenetic regulation. The study identified over 34,000 genomic regions exhibiting distinct ON/OFF methylation patterns of both copies of the genome, or allele-specific methylation.
The authors identified cell-type-specific patterns that provide valuable insights into how epigenetic modifications can influence gene expression and may help explain the unique inheritance patterns observed in conditions such as CHARGE syndrome (a rare genetic disorder characterized by a combination of birth defects that affect multiple body systems).
By analyzing sorted samples representing a wide range of healthy human cell types, and using advanced machine learning algorithms and genetic information to disentangle the methylation patterns of the two parental copies of DNA, the team precisely identified hundreds of “imprinted” regions—where the maternal allele is methylated and silenced while the paternal allele is active, or vice versa.
This is published in Nature Communications in the paper, “Atlas of imprinted and allele-specific DNA methylation in the human body.”
“Genomic imprinting is set early during development, and the common dogma was that it is then maintained throughout life across all cell types. Yet, our atlas not only confirms most previously known imprinted regions, but we also identified many novel regions showing parental imprinting in a cell-type-specific manner,” explained Tommy Kaplan, PhD, from the School of Computer Science and Engineering at the Hebrew University of Jerusalem and Hadassah Medical Center. “These findings open new avenues for investigating how parental methylation influences gene regulation and the development of certain diseases.”
Using machine learning algorithms and deep whole-genome bisulfite sequencing on freshly isolated and purified cell populations, the study unveils a detailed landscape of genetic and epigenetic regulation that could reshape our understanding of gene expression and disease.
A key focus of the research is the success in identifying differences between the two alleles and, in some cases, demonstrating that these differences result from genomic imprinting (whether the allele is inherited from the mother or the father).
The team identified 325,000 genomic regions—approximately 6% of the genome and 11% of CpG sites—that exhibit a bimodal pattern of fully methylated and fully unmethylated molecules. In 34,000 of these regions, genetic variations (SNPs) correlate with the methylation patterns, confirming allele-specific methylation and indicating the extent of genetic influence on DNA methylation.
The researchers detected 460 regions with parental allele-specific methylation, including hundreds of previously unknown imprinted regions. They also found evidence that both sequence-dependent and parental allele-specific methylation are frequently unique to specific tissues or cell types, revealing previously unappreciated diversity in epigenetic regulation across the human body.
Validation of tissue-specific, maternal allele-specific methylation of the CHD7 gene suggests a potential mechanism for the paternal bias observed in CHARGE syndrome inheritance.
“The discovery of tissue-specific imprinting, such as that observed in CHD7, highlights the dynamic nature of epigenetic regulation,” noted Yuval Dor, PhD, faculty of medicine at the Hebrew University of Jerusalem and Hadassah Medical Center. “This could have implications for understanding some autosomal dominant diseases and for developing innovative diagnostic tools.”
The atlas represents a valuable resource for the scientific community, offering a platform for further computational and molecular analyses of allele-specific methylation. Its insights may lead to novel strategies for diagnosing imprinting-related disorders and exploring therapeutic interventions based on tissue-specific epigenetic profiles.
By integrating DNA methylation and gene expression data from a wide range of tissues and cell types, this atlas not only deepens our understanding of the mechanisms underlying gene regulation but also serves as a critical resource for future research into the interplay between genetics and epigenetics in disease development and progression.