Genomic Imprinting at the Transcriptional Level

Abstract

Abstract Genomic imprinting is an epigenetic mechanism of gene regulation that causes genes to be expressed from only one of the two parentally inherited chromosomes in mammals. This form of regulation affects less than 1% of genes and has crucial roles in embryonic growth, development and brain function. Imprinted genes are often clustered in large chromosomal domains and their expression is regulated by cis ‐acting imprinting control regions (ICRs). ICRs carry a methylation imprint that is laid down in one of the two parental germlines, when the two genomes are separated, to distinguish the paternal and the maternal alleles. To date, 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 (ncRNAs). Aberrant expression of imprinted genes leads to human pathologies and is frequent in cancer. Genomic imprinting provides a unique model for studying the epigenetic influence on transcriptional activity and repression. Key Concepts: A subset of genes in the mammalian genome (less than 1%) known as imprinted genes are expressed exclusively from one of the two parental alelles. The existence of genomic imprinting highlights the nonequivalence of parental genomes and precludes the viability of mammalian embryos with exclusive contribution of genetic material from one of the parents. Imprinted genes are involved in fetal growth and placental development in the uterus, as well as brain function and metabolism in adults. Genomic imprinting has been reported in placental mammals and marsupials but not in montremes. Most imprinted genes are physically linked in chromosomal regions known as imprinted clusters and are co‐ordinatively regulated. Genomic imprinting at clusters is regulated by imprinting control regions (ICRs) that acquired an imprint distinguishing the two parental alelles during gametogenesis. DNA methylation is the bona fide imprint mark that distinguishes the two parental alleles at the ICRs, resisting the wave of DNA demethylation after fertilisation and being erased and reset in the germline. 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 non‐coding RNAs explains the imprinting regulation for at least three imprinted clusters by yet unknown mechanisms. Deregulation of genomic imprinting can cause imprinted disorders in humans which exhibit parent of origin effects in their pattern of inheritance.