Imprinted Genes and Multiple Sclerosis: What Do We Know?

Abstract

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disease of the central nervous system that arises from interplay between non-genetic and genetic risk factors. The epigenetics functions as a link between these factors, affecting gene expression in response to external influence, and therefore should be extensively studied to improve the knowledge of MS molecular mechanisms. Among others, the epigenetic mechanisms underlie the establishment of parent-of-origin effects that appear as phenotypic differences depending on whether the allele was inherited from the mother or father. The most well described manifestation of parent-of-origin effects is genomic imprinting that causes monoallelic gene expression. It becomes more obvious that disturbances in imprinted genes at the least affecting their expression do occur in MS and may be involved in its pathogenesis. In this review we will focus on the potential role of imprinted genes in MS pathogenesis.

Keywords: DLK1-DIO3 locus; genomic imprinting; miRNA; multiple sclerosis; parent-of-origin effect.

Figure 1

The schematic representation of the locus DLK1-DIO3 (based on genome assembly GRCh38.p12). The imprinted locus DLK1-DIO3 contains paternally-expressed protein-coding genes: DLK1, DIO3, and RTL1 genes (blue rectangles) and maternally-expressed genes of long noncoding RNAs: MEG3, MEG8, MEG9, and RTL1AS (red rectangles). MEG8 contains a tandemly repeating array of small nucleolar RNAs (snoRNAs) of C/D-box family, namely SNORD112, SNORD113, and SNORD114, consisting of one, nine, and 31 paralogous genes of snoRNAs, respectively. The locus also includes two large clusters of microRNA (miRNA) genes (10 miRNA genes in 14q32.2 and 44 miRNA genes in 14q32.31), expressed from the maternal allele. IG-DMR and MEG3-DMR are methylated on the paternal chromosome, while MEG8-DMR, in contrast, is methylated on the maternal chromosome. Filled ellipses represent methylated DMRs, and open ellipses represent unmethylated DMRs. Gray boxes and black strokes indicate non-expressing genes. Transcriptionally-active genes are marked with colored boxes and strokes; purple and red strokes are miRNA and snoRNA genes, respectively.

Figure 2

The schematic representation of IGF2-H19 imprinted locus (based on genome assembly GRCh38.p12). On the paternal allele, methylation of H19-DMR directly blocks the promoter of H19 gene, but does not prevent 3′ enhancers from activating transcription of IGF2, IGF2-AS, and MIR483 genes. On the maternal unmethylated allele, transcriptional repressor CTCF can bind to the ICR overlapping with H19-DMR and block IGF2 promoter. The enhancer can still efficiently activate the unmethylated H19 promoter and induce expression of both H19 and located in it MIR483. Dark ellipse represents fully methylated “primary” H19-DMR, open ellipse represent unmethylated “primary” DMR; light colored ellipses are for “secondary” somatic IGF2-DMR0 and IGF2-DMR2, differentially methylated on paternal and maternal chromosomes only in several tissues. Gray boxes and black strokes indicate non-expressing genes. Transcriptionally-active genes are marked with colored boxes and purple strokes.

Figure 3

The schematic representation of RB1 imprinting (based on genome assembly GRCh38.p12). Unmethylated E2B-DMR on the paternal allele activates expression of RB1-2B, which acts as a roadblock for the regular RB1 transcript on the same allele, while methylation of E2B-DMR on maternal allele allows normal expression of RB1. Filled ellipse represents methylated E2B-DMR, and open ellipses represent unmethylated DMRs. Dark and light boxes indicate exons and introns of RB1 gene, respectively.