The correlation between CpG methylation and gene expression is driven by sequence variants

Area of Science:

• Genomics
• Epigenetics
• Molecular Biology

Background:

• Gene promoter and enhancer sequences are typically unmethylated at CpG sites, correlating with gene expression.
• DNA methylation is understood to play a regulatory role in gene expression.

Purpose of the Study:

• To investigate haplotype-specific methylation rates across millions of CpG units in whole-blood genomes.
• To identify methylation-depleted sequences and their association with genetic variants.
• To determine the role of DNA sequence variation in allele-specific methylation and gene expression.

Main Methods:

• Utilized nanopore sequencing to determine methylation rates for 15.3 million CpG units across 7,179 whole-blood genomes.
• Identified 189,178 methylation-depleted sequences (three or more proximal CpGs unmethylated on at least one haplotype).
• Performed RNA sequencing on 896 samples to correlate methylation patterns with gene expression.

Main Results:

• Discovered 77,789 methylation-depleted sequences associated with 80,503 cis-acting sequence variants, termed allele-specific methylation quantitative trait loci (ASM-QTLs).
• Demonstrated that ASM-QTLs (DNA sequence variability) drive the correlation between gene expression and CpG methylation.
• Found ASM-QTLs to be significantly enriched among variants associated with hematological traits (40.2-fold enrichment).

Conclusions:

• ASM-QTLs are crucial functional elements in the noncoding genome, linking DNA sequence variation to epigenetic regulation.
• DNA sequence variability, as captured by ASM-QTLs, is a primary driver of allele-specific gene expression influenced by DNA methylation.
• These findings highlight the importance of ASM-QTLs in understanding the genetic and epigenetic basis of complex traits, particularly hematological ones.