A Novel CpG Island Set Identifies Tissue-Specific Methylation at Developmental Gene Loci

TLDR

CpG islands are dense CpG clusters that punctuate the CpG‑deficient human genome and associate with many gene promoters. The authors devised a CGI enrichment method based on nonmethylated CpG affinity chromatography to study methylation patterns. The study used nonmethylated CpG affinity chromatography to enrich CGIs, sequenced the library to create a novel blood CGI set, and profiled methylation across tissues with a 17,000‑CGI array. About half of CGIs overlap transcription start sites, 6–8 % are methylated in blood, brain, muscle, and spleen, with inter‑ and intragenic CGIs more susceptible, and tissue‑specific methylation is enriched at developmental loci such as HOX and PAX, providing a basis for studying CGI methylation in health and disease.

Abstract

CpG islands (CGIs) are dense clusters of CpG sequences that punctuate the CpG-deficient human genome and associate with many gene promoters. As CGIs also differ from bulk chromosomal DNA by their frequent lack of cytosine methylation, we devised a CGI enrichment method based on nonmethylated CpG affinity chromatography. The resulting library was sequenced to define a novel human blood CGI set that includes many that are not detected by current algorithms. Approximately half of CGIs were associated with annotated gene transcription start sites, the remainder being intra- or intergenic. Using an array representing over 17,000 CGIs, we established that 6%–8% of CGIs are methylated in genomic DNA of human blood, brain, muscle, and spleen. Inter- and intragenic CGIs are preferentially susceptible to methylation. CGIs showing tissue-specific methylation were overrepresented at numerous genetic loci that are essential for development, including HOX and PAX family members. The findings enable a comprehensive analysis of the roles played by CGI methylation in normal and diseased human tissues.