Genomic Imprinting at the Transcriptional Level

Abstract

Abstract Genomic imprinting is an epigenetic mechanism of gene regulation causing genes to be expressed from only one of the two parentally inherited chromosomes in mammals. Imprinted genes often cluster in large chromosomal domains and their expression is regulated by cis ‐acting imprinting control regions. These regions carry an epigenetic imprint, mostly in the form of deoxyribonucleic acid methylation, laid down during gametogenesis, when the two genomes are separated. Regulation of imprinting in these clusters is thought to be explained by competition of promoters of different genes to common enhancers or cis ‐regulation induced by long noncoding RNAs. Aberrant expression of imprinted genes leads to human pathologies characterised by mental, developmental and metabolic abnormalities. Imprinting errors are also often seen in stem cells, including induced pluripotent stem cells and affect their physiology and pluripotent potential. For these reasons, genomic imprinting remains a crucial model for understanding the epigenetic influence on transcriptional activity and repression. Key Concepts A subset of genes in the mammalian genome (<1%) known as imprinted genes are expressed exclusively from one of the two parental alleles. Imprinted genes are involved in foetal growth and placental development in the uterus, as well as brain function and metabolism in adults. Most imprinted genes are physically linked in chromosomal regions known as imprinted clusters and are coordinatively regulated. Genomic imprinting at clusters is regulated by imprinting control regions (ICRs) that acquired an imprint distinguishing the two parental alleles during gametogenesis. DNA methylation is the bona fide imprint mark at ICRs, but chromatin modifications, such as H3K27me3, also serve as an imprint mark at transient and/or placental‐specific ICRs. Methylation imprints are established in the parental germ line, resist the wave of DNA demethylation after fertilisation and are erased before resetting in the germ line according to the sex. Insulation of common enhancers by the methylated sensitive protein Ctcf explains the imprinting regulation at the Igf2/H19 region. Silencing of genes in cis by long noncoding RNAs (lncRNAs) explains the imprinting regulation of, at least, three clusters through transcription interference and recruitment of chromatin modifiers. Deregulation of genomic imprinting can cause imprinted disorders in humans, which exhibit parent of origin effects in their pattern of inheritance. Imprinting defects occur in stem cells and during somatic reprogramming into induced pluripotent stem cells (iPSCs) affecting their pluripotency and harness their potential clinical applications.