A well-illustrated map may have helped the Spanish easily locate El Dorado or David Livingstone pinpoint the source of the Nile; now, rugged researchers have delicately “sliced” through the jungle of the human genome to create a map of imprint control regions (ICRs) – creating the “imprintome” – to hasten our exploration of the epigenetic roots of disease.
DNA methylation at ICRs helps to regulate the allele-specific expression of the imprinted genes that control human development; however, only 25 ICRs regulating 100–150 human imprinted genes (of the 300–1,000 predicted) have been described. Interestingly, DNA methylation profiles display similarities across cell types due to ICR establishment before tissue specification; therefore, ICR analysis could help explore the epigenetic roots of human disease, given that altered DNA methylation at ICRs has been linked to adult-onset disease with fetal origins. Now, eager explorers led by Randy L. Jirtle and Cathrine Hoyo (North Carolina State University, USA) report the genome-wide mapping of human ICRs – through combined DNA methyl-sequencing in various tissues and bioinformatic analysis – to create the human “imprintome.”
Let’s hear from Jima and Colleagues on how ICR mapping may help us to explore the epigenetic roots of human disease:
- The authors report a human imprintome comprising 1,488 hemi-methylated cis-acting CpG sites as candidate ICRs
- 332 ICRs display parent-of-origin specific methylation – 178 paternally and 154 maternally methylated
- 209/332 ICRs overlap DNase I hypersensitive regions, suggesting gene regulatory abilities
- ICRs display a median CpG content of 248 (like the 25 characterized ICRs), with a size range of 10-4,000 bp
- As chromosomes frequently contain clusters of genes controlled by a single ICR (i.e., imprinted domains), 332 ICRs could regulate the expression of more than 500 imprinted genes (around 3% of the genome)
- The majority of ICRs lie close to genes involved in fundamental biological processes, including cAMP biosynthetic processes, cellular responses to glucagon, and adenylate cyclase-activating G protein-coupled receptor signaling
- A substantial proportion of candidate ICRs also lie near genes involved in metabolic and neurological diseases
- The authors report the creation of an online imprintome browser linked to the UCSC Genome Browser to visualize all data associated with this genome-wide map of ICRs – head over to https://humanicr.org to start exploring
These adventurous authors anticipate that exploring their genomic map of ICRs – or the human imprintome – will help explain the epigenetic basis of normal development, describe the epigenetic dysregulation that underlies diseases of fetal origin, and potentially diagnose, treat, and even prevent developmental disorders.
Some final thoughts from co-expedition leader Randy L. Jirtle: “The imprintome consists of the hemimethylated genomic regions that control monoallelic expression of imprinted genes; it is not the repertoire of these genes. A novel tool for scientists, the human imprintome, will help elucidate the role of imprinted genes in the development of diseases and disorders and in the evolution of mammals.”
For how a genome-wide map of ICRs will help us to explore the epigenetic roots of disease, see Epigenetics, July 2022.