The influence of DNA methylation on monoallelic expression

Abstract

Monoallelic gene expression occurs in diploid cells when only one of the two alleles of a gene is active. There are three main classes of genes that display monoallelic expression in mammalian genomes: (1) imprinted genes that are monoallelically expressed in a parent-of-origin dependent manner; (2) X-linked genes that undergo random X-chromosome inactivation in female cells; (3) random monoallelically expressed single and clustered genes located on autosomes. The heritability of monoallelic expression patterns during cell divisions implies that epigenetic mechanisms are involved in the cellular memory of these expression states. Among these, methylation of CpG sites on DNA is one of the best described modification to explain somatic inheritance. Here, we discuss the relevance of DNA methylation for the establishment and maintenance of monoallelic expression patterns among these three groups of genes, and how this is intrinsically linked to development and cellular states.

Keywords: DNA methylation; X-chromosome inactivation; epigenetics; imprinting; monoallelic expression.

Figure 1. Genomic imprinting regulation by parental allele-specific DNA methylation

(A) The imprinting cycle: the scheme illustrates the overall changes in DNA methylation at ICRs (both at ICRs methylated on the maternal inherited allele and unmethylated on the paternal inherited allele and vice versa) from PGC (primordial germ cells), mature germ cells (sperm and oocyte), zygote, blastocyst to the adult mouse; overall methylation status is simplified in two states represented with graded colours for both the maternally and paternally inherited chromosomes: maternal/paternal chromosome corresponds to normal methylation levels of somatic cells; hypomethylated maternal/paternal chromosomes correspond to reduced methylation levels upon major waves of DNA demethylation. (B) Representation of Igf2-H19 and Kcnq1/Kcnq1ot1 imprinted clusters on distal end of mouse chromosome 7 or on human 11p15.5 chromosomal region. Igf2-H19 imprinting is regulated by the H19 DMR, an intergenic ICR methylated on the paternal allele and unmethylated on the maternal allele; the unmethylated allele is bound by CTCF, which is involved in 3D chromatin looping and important for imprinting regulation at this cluster; the methylated allele is bound by both ZFP57 and/or ZFP445 that are crucial to protect the methylated state during the major epigenetic remodelling observed in pre-implantation stages. The Kcnq1/Kcnq1ot1 cluster is represented here in a simplified fashion; this imprinted cluster is regulated by the KvDMR, an ICR located at the promoter of the Kcnq1ot1 lncRNA, which is methylated and bound by ZFP57 and/or ZFP445 on the maternal allele. Paternally expressed Kcnq1ot1 lncRNA is believed to recruit Polycomb repressive complexes 1 and 2 (PRC1/2) (dashed arrows) to silence protein-coding genes such as Kcnq1 and Cdkn1c. This scheme is not drawn to scale.

Figure 2. DNA methylation during XCI

(A) DNA methylation profiles of the active and inactive X chromosomes illustrating the hypermethylation of promoter-CGIs linked to genes undergoing XCI on the Xi (orange/grey boxes), hypomethylation of promoter-CGI associated with escape genes (green boxes), gene-body methylation associated with gene expression on both Xa and Xi and hypomethylation of CpG sites on the Xi compared with Xa. (B) Illustration of the mechanisms involved in methylation of the Xi. DNMT3B establishes methylation of all CGI on the Xi (fast and slow methylating, as well as intergenic CGI). The mechanism of DNMT3 recruitment to the Xi remains unknown, but it is believed to be partially dependent on SMCHD1 function in chromatin architecture. Slow methylating islands are dependent on SMCHD1 for their methylation, whereas fast islands acquire methylation mostly independently of SMCHD1, defining a parallel unknown pathway. Abbreviation: SMCHD1, structural maintenance of chromosomes hinge domain-containing 1.

Figure 3. Allele-specific DNA methylation imbalances associated with RME or with DNA sequence polymorphisms

(A) Schematic representation of the possible allele-specific expression states for an RME gene whose expression shows good correlation with DNA methylation levels. A cell population with four representative cells are shown. The RME gene is expressed from the unmethylated paternal allele in blue cells, from the unmethylated maternal in red cells, biallelically expressed in purple cells and not expressed in grey cells. (B) Schematic representation of allele-specific DNA methylation (ASM) associated with DNA sequence polymorphisms and allele-specific expression imbalance in two individuals. Here, the methylation status and the allelic expression are dependent on cis-acting polymorphisms.