Imprinted Genes and Multiple Sclerosis: Comparison
Please note this is a comparison between versions V1 by Natalia Baulina and V2 by Rita Xu.

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 - the study of heritable changes in gene expression that do not involve changes in the primary DNA sequence or genotype - functions as a link between these factors, affecting gene expression in response to external influence. 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 affecting their expression do occur in MS and may be involved in its pathogenesis. 

  • multiple sclerosis
  • parent-of-origin effect
  • genomic imprinting
  • DLK1-DIO3 locus
  • miRNA

Note:All the information in this draft can be edited by authors. And the entry will be online only after authors edit and submit it.

1. Introduction

Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease of the central nervous system (CNS) in which inflammation, demyelination, and axonal degeneration lead to a fast progression of neurological disability in young adults [1]. MS is a relatively common disease affecting about 1 in 1000 individuals in Europe and North America [2]. In the last few decades, its prevalence has increased substantially due to not only improved diagnostics and survival of patients, but also the rise of MS incidence [3], which contributes to the high social and economic importance of the disease. Demographic studies have shown that MS, like many other autoimmune diseases, is about 2 times more common in women than in men. Moreover, women are diagnosed with MS 1–2 years earlier than men, but men are more likely to develop a more severe MS course.

The clinical course of MS is highly heterogeneous. Most patients have relapsing-remitting MS (RRMS), which is characterized by recurrent acute exacerbations followed by partial or complete recovery, and, with time, they develop secondary progressive MS (SPMS), specified by gradual accumulation of irreversible impairment. Ten to fifteen percent of patients have so-called primary progressive MS (PPMS) with a steady increase of the irreversible neurological dysfunction from onset [4]. To date, RRMS is the most well studied MS course due to its highest prevalence.

MS is a complex disease that arises from interplay between non-genetic and genetic risk factors. Lifestyle and environmental factors, such as Epstein-Barr infection, vitamin D deficiency, smoking, as well as changes in sex hormone profiles are among the best-established non-genetic risk factors of MS [5][6][5,6]. The HLA locus on chromosome 6 is known as the main marker of genetic susceptibility to the disease; beyond it, more than 200 other loci affecting MS risk are currently identified. At the same time, their cumulative contribution cannot explain more than 48% of MS heritability [7].

Epigenetic changes affecting gene expression in response to external influence represent the link between non-genetic and genetic risk factors, which should be extensively studied to improve the knowledge of MS molecular mechanisms. Epigenetic mechanisms are involved in the establishment of parent-of-origin effects (POEs) that appear as phenotypic differences depending on whether the allele was inherited from the mother or father [8]. The parental transmission of alleles is accomplished by mechanisms other than classical Mendelian segregation of nuclear genes [9].

2. Parent-Of-Origin Effects in MS Development

POEs could be determined as effects that arise (1) from the epigenetic regulation of gene expression (such as genomic imprinting, GI—one of the best characterized POE); (2) from the effects of the maternal intrauterine environment on the developing fetus; and (3) from genetic variation in the maternally inherited mitochondrial genome. POEs were until recently almost exclusively discussed in the context of classical diseases of GI, but they are now receiving recognition in a wider range of complex diseases, including MS. Studying POEs in MS is tricky since the establishment of its impact on the disease is influenced by environmental and in utero effects and requires a large population of phenotyped individuals of varying degrees of relatedness, whose genotypes are assigned with parental origin. However it is believed that POEs hold the potential to explain “hidden” heritability to MS.

The increased risk for MS in children of affected mothers was described [10]. A number of studies demonstrated POE for HLA locus, where a significant over transmission of HLA-DRB1*15 from mothers was observed [11][12][11,12].

A reciprocal backcross study in rats with experimental autoimmune encephalomyelitis (EAE), the widely-accepted animal model of MS, demonstrated that 37–54% of EAE susceptibility loci depended on parental transmission; these loci overlapped with experimentally confirmed or predicted imprinted genes [13]. Similarly, a study in mice showed that several loci were predisposed for EAE in a parent-of-origin-dependent manner [14].

3. The Genomic Basis of Imprinting

GI is epigenetically regulated POE in placental mammals that cause monoallelic gene expression. Most of the known imprinted genes are characterized by monoallelic expression in all tissues, but about 28% exhibit monoallelic expression in only one or several tissues, i.e., are imprinted in a tissue-specific manner [15][16][17][15–17]. The genes are imprinted depending on the stage of ontogenesis, i.e., imprinted in a stage-specific manner, being biallelically expressed early in development and undergoing only monoallelic expression at later embryonic stages, or vice versa [18][19][20][18–20]. For a few imprinted genes a reversal imprinting was demonstrated: The gene is expressed from the maternal allele in some tissues or developmental stages, and from the paternal allele in others [21][22][23][21–23].

Many imprinted genes tend to group into extended clusters from hundreds to thousands of bp in length, the so-called imprinted loci, within which there is a coordinated regulation of gene expression [24]. The imprinted loci may include paternal and maternal expressed genes. The structure of the imprinted loci always includes protein coding genes, long noncoding RNA genes, and, commonly, small noncoding RNA genes: MicroRNA (miRNA) and small nucleolar RNA [25]. It is known that genes of non-coding RNA (both long and small) are involved in regulatory processes. Thus, long non-coding RNAs are important regulators of gene expression, organizing nuclear architecture and regulating transcription; they also modulate mRNA stability and translation, and are involved in the process of posttranscriptional modifications in the cytoplasm [26]. MiRNAs, single-stranded short non-coding RNAs, are involved in posttranscriptional regulation of gene expression due to complete or partially complete sequence complementarity between miRNA and target mRNA, which leads to mRNA degradation or inhibition of its translation [27]. Small nucleolar RNAs are mainly involved in posttranscriptional modifications and maturation of rRNA, tRNA, and small nuclear RNAs, as well as in the regulation of alternative splicing [28].

The monoallelic gene expression at the imprinted loci is controlled by independent imprinting control regions (ICRs). ICRs are characterized by the presence of germline differentially methylated regions (DMRs)—CpG-rich sequences, the methylation of which is carried out on one of the parental chromosomes at the stage of gametogenesis [29]. These DMRs direct alternative splicing, regulate the rate of transcription elongation, or select alternative polyadenylation sites, leading to the synthesis of various allele-specific isoforms of transcripts [30][31][30,31]. To date, 35 such germline DMRs have been identified in the human genome [32]. In humans most of them are methylated in female gametes, and only three DMRs (in H19/IGF2, MEG3/DLK1 and ZDBF2/GPR1-AS imprinted loci) are known to be methylated in male gametes. In addition to these “primary” germline DMRs in the ICRs, imprinted loci can also contain so-called “somatic”, or “secondary” DMRs in which parent-specific methylation is established after fertilization. These “secondary” DMRs are found in the promoters of some imprinted genes or transcription factors’ binding sites [30]. Methylation status of “secondary” DMRs is usually guided by “primary” DMRs.

Long non-coding RNAs [33], insulator proteins [34], and also histone modification [35] take part in the regulation of imprinting together with DNA methylation. Moreover, the products of imprinted genes interact with each other, forming networks, and, thus, participate in a finer tuning of imprinting regulation; it is known that a dysfunction of one imprinted gene can affect other genes expressed from the maternal or paternal alleles [36][37][36,37]. The existence of such a network may partially explain the fact that all hereditary GI disorders are characterized by common clinical features, affecting development, growth, behavior, and metabolism [38][39][38,39].

By today, disturbances in imprinted genes are found in the pathogenesis of complex diseases, among which cancer is the most studied [40]. Such disturbances may also be involved in the development of several autoimmune and neurodegenerative disorders [41][42][43][41–43], including MS [13][44][45][13,44,45]. MS is not a “classic” GI disorder. Nevertheless, it becomes more obvious that disturbances in imprinted genes at the least affecting their expression do occur in MS, as well as in other polygenic diseases, and may be involved in its pathogenesis. Therefore, a promising way of studying MS development may be the search for disturbances in known imprinted genes.


  1. Oh, J.; Vidal-Jordana, A.; Montalban, X. Multiple sclerosis: Clinical aspects. Opin. Neurol. 2018, 31, 752–759, doi:10.1097/WCO.0000000000000622.
  2. Oksenberg, J.R. Decoding multiple sclerosis: An update on genomics and future directions. Rev. Neurother. 2013, 11–19, doi:10.1586/14737175.2013.865867.
  3. Wallin, M.T.; Culpepper, W.J.; Nichols, E.; Bhutta, Z.A.; Gebrehiwot, T.T.; Hay, S.I.; Khalil, I.A.; Krohn, K.J.; Liang, X.; Naghavi, M.; et al. Global, regional, and national burden of multiple sclerosis 1990–2016: A systematic analysis for the Global Burden of Disease Study. Lancet Neurol. 2019, 18, 269–285, doi:10.1016/S1474-4422(18)30443-5.
  4. Bramow, S.; Frischer, J.M.; Lassmann, H.; Koch-Henriksen, N.; Lucchinetti, C.F.; Sørensen, P.S.; Laursen, H. Demyelination versus remyelination in progressive multiple sclerosis. Brain 2010, 133, 2983–2998, doi:10.1093/brain/awq250.
  5. Ascherio, A.; Munger, K.L. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Neurol. 2007,61, 504–513, doi:10.1002/ana.21141.
  6. Ascherio, A., Munger KL. Environmental risk factors for multiple sclerosis. Part I: The role of infection. Neurol. 2007, 61, 288–299, doi:10.1002/ana.21117.
  7. Patsopoulos, N.A.; Baranzini, S.E.; Santaniello, A.; Shoostari, P.; Cotsapas, C.; Wong, G.; Beecham, A.H.; James, T.; Replogle, J.; Vlachos, I.S.; et al. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 2019, 80, 365, doi:10.1126/science.aav7188.
  8. Lawson, H.A.; Cheverud, J.M.; Wolf, J.B. Genomic imprinting and parent-of-origin effects on complex traits. Rev. Genet. 2013, 14, 609–617, doi:10.1038/nrg3543.
  9. Rampersaud, E.; Mitchell, B.; Naj, A.; Pollin, T. Investigating Parent of Origin Effects in Studies of Type 2 Diabetes and Obesity. Diabetes Rev. 2008, 4, 329–339, doi:10.2174/157339908786241179.
  10. Sadovnick, A.D.; Yee, I.M.L.; Ebers, G.C. Factors influencing sib risks for multiple sclerosis. Genet. 2000, 58, 431–435, doi:10.1034/j.1399-0004.2000.580602.x.
  11. Chao, M.J.; Ramagopalan, S.V.; Herrera, B.M.; Lincoln, M.R.; Dyment, D.A.; Sadovnick, A.D.; Ebers, G.C. Epigenetics in multiple sclerosis susceptibility: Difference in transgenerational risk localizes to the major histocompatibility complex. Mol. Genet. 2009, 18, 261–266, doi:10.1093/hmg/ddn353.
  12. Ramagopalan, S.V.; Herrera, B.M.; Bell, J.T.; Dyment, D.A.; DeLuca, G.C.; Lincoln, M.R.; Orton, S.M.; Chao, M.J.; Sadovnick, A.D.; Ebers, G.C. Parental transmission of HLA-DRB1*15 in multiple sclerosis. Genet. 2008, 122, 661–663, doi:10.1007/s00439-007-0442-z.
  13. Stridh, P.; Ruhrmann, S.; Bergman, P.; Thessén Hedreul, M.; Flytzani, S.; Da Beyeen, A.; Gillett, A.; Krivosija, N.; Öckinger, J.; Ferguson-Smith, A. C.; et al. Parent-of-Origin Effects Implicate Epigenetic Regulation of Experimental Autoimmune Encephalomyelitis and Identify Imprinted Dlk1 as a Novel Risk Gene. PLoS Genet. 2014, 10, doi:10.1371/journal.pgen.1004265.
  14. Encinas, J.A.; Lees, M.B.; Sobel, R.A.; Symonowicz, C.; Weiner, H.L.; Seidman, C.E.; Seidman, J.G.; Kuchroo, V. K. Identification of genetic loci associated with paralysis, inflammation and weight loss in mouse experimental autoimmune encephalomyelitis. Immunol. 2001, 13, 257–264, doi:10.1093/intimm/13.3.257.
  15. Hudson, Q.J.; Kulinski, T.M.; Huetter, S.P.; Barlow, D.P. Genomic imprinting mechanisms in embryonic and extraembryonic mouse tissues. Heredity 2010, 105, 45–56, doi:10.1038/hdy.2010.23.
  16. Prickett, A.R.; Oakey, R.J. A survey of tissue-specific genomic imprinting in mammals. Gen. Genom. 2012, 287, 621–630, doi:10.1007/s00438-012-0708-6.
  17. Baran, Y.; Subramaniam, M.; Biton, A.; Tukiainen, T.; Tsang, E.K.; Rivas, M.A.; Pirinen, M.; Gutierrez-Arcelus, M.; Smith, K.S.; Kukurba, K. R.; et al. The landscape of genomic imprinting across diverse adult human tissues. Genome Res. 2015, 25, 927–936, doi:10.1101/gr.192278.115.
  18. Yamasaki, Y.; Kayashima, T.; Soejima, H.; Kinoshita, A.; Yoshiura, K.I.; Matsumoto, N.; Ohta, T.; Urano, T.; Masuzaki, H.; Ishimaru, T.; et al. Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air. Mol. Genet. 2005, 14, 2511–2520, doi:10.1093/hmg/ddi255.
  19. Lerchner, W.; Barlow, D.P. Paternal repression of the imprinted mouse Igf2r locus occurs during implantation and is stable in all tissues of the post-implantation mouse embryo. Dev. 1997, 61, 141–149, doi:10.1016/S0925-4773(96)00630-2.
  20. Szabó, P.E.; Mann, J.R. Allele-specific expression and total expression levels of imprinted genes during early mouse development: Implications for imprinting mechanisms. Genes Dev. 1995, 9, 3097–3108, doi:10.1101/gad.9.24.3097.
  21. Kota, S.K.; Llères, D.; Bouschet, T.; Hirasawa, R.; Marchand, A.; Begon-Pescia, C.; Sanli, I.; Arnaud, P.; Journot, L.; Girardot, M.; et al. ICR noncoding RNA expression controls imprinting and DNA replication at the Dlk1-Dio3 domain. Cell. 2014, 31, 19–33, doi:10.1016/j.devcel.2014.08.009.
  22. Sanz, L.A.; Chamberlain, S.; Sabourin, J.C.; Henckel, A.; Magnuson, T.; Hugnot, J.P.; Feil, R.; Arnaud, P. A mono-allelic bivalent chromatin domain controls tissue-specific imprinting at Grb. EMBO J. 2008, 27, 2523–2532, doi:10.1038/emboj.2008.142.
  23. Arnaud, P.; Monk, D.; Hitchins, M.; Gordon, E.; Dean, W.; Beechey, C.V.; Peters, J.; Craigen, W.; Preece, M.; Stanier, P.; et al. Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark. Mol. Gen. 2003, 12, 1005–1019, doi:10.1093/hmg/ddg110.
  24. Edwards, C.A.; Ferguson-Smith, A.C. Mechanisms regulating imprinted genes in clusters. Opin. Cell Biol. 2007, 19, 281–289, doi:10.1016/
  25. Royo, H.; Cavaillé, J. Non-coding RNAs in imprinted gene clusters. Cell. 2008, 100, 149–166, doi:10.1042/bc20070126.
  26. Yao, R.W.; Wang, Y.; Chen, L.L. Cellular functions of long noncoding RNAs. Cell Biol. 2019, 21, 542–551, doi:10.1038/s41556-019-0311-8.
  27. O’Brien, J.; Hayder, H.; Zayed, Y.; Peng, C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Endocrinol. 2018, 9, 402, doi:10.3389/fendo.2018.00402.
  28. Liang, J.; Wen, J.; Huang, Z.; Chen, X.; Zhang, B.; Chu, L. Small Nucleolar RNAs: Insight Into Their Function in Cancer. Oncol. 2019, 9, doi:10.3389/fonc.2019.00587.
  29. Abramowitz, L.K.; Bartolomei, M.S. Genomic imprinting: Recognition and marking of imprinted loci. Opin. Gen. Dev. 2012, 22, 72–78, doi:10.1016/j.gde.2011.12.001.
  30. Zink, F.; Magnusdottir, D.N.; Magnusson, O.T.; Walker, N.J.; Morris, T.J.; Sigurdsson, A.; Halldorsson, G.H.; Gudjonsson, S. A.; Melsted, P.; Ingimundardottir, H.; et al. Insights into imprinting from parent-of-origin phased methylomes and transcriptomes. Genet. 2018, 50, 1542–1552, doi:10.1038/s41588-018-0232-7.
  31. Niemczyk, M.; Ito, Y.; Huddleston, J.; Git, A.; Abu-Amero, S.; Caldas, C.; Moore, G. E.; Stojic, L.; Murrell, A. Imprinted chromatin around DIRAS3 regulates alternative splicing of GNG12-AS1, a long noncoding RNA. J. Hum. Genet. 2013, 93, 224–235, doi:10.1016/j.ajhg.2013.06.010.
  32. Monk, D.; Morales, J.; den Dunnen, J.T.; Russo, S.; Court, F.; Prawitt, D.; Murrell, A.; Friess, H.; Reik, W.; Stanier, P.; et al. Recommendations for a nomenclature system for reporting methylation aberrations in imprinted domains. Epigenetics 2018, 13, 117–121, doi:10.1080/15592294.2016.1264561.
  33. Kanduri, C. Long noncoding RNAs: Lessons from genomic imprinting. Biophys. Acta Gene Regul. Mech. 2016, 1859, 102–111, doi:10.1016/j.bbagrm.2015.05.006.
  34. Tan, L.; Xing, D.; Chang, C.H.; Li, H.; Xie, X.S. Three-dimensional genome structures of single diploid human cells. Science 2018, 361, 924–928, doi:10.1126/science.aat5641.
  35. Rao, S.S.P.; Huntley, M.H.; Durand, N.C.; Stamenova, E.K.; Bochkov, I.D.; Robinson, J.T.; Sanborn, A.L.; Machol, I.; Omer, A.D.; Lander, E. S.; et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 2014, 159, 1665–1680, doi:10.1016/j.cell.2014.11.021.
  36. Gabory, A.; Ripoche, M.A.; Le Digarcher, A.; Watrin, F.; Ziyyat, A.; Forné, T.; Jammes, H.; Ainscough, J.F.X.; Surani, M. A.; Journot, L.; et al. H19 acts as a trans regulator of the imprinted gene network controlling growth in mice. Development 2009, 136, 3413–3421, doi:10.1242/dev.036061.
  37. Stelzer, Y.; Sagi, I.; Yanuka, O.; Eiges, R.; Benvenisty, N. The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome. Genet. 2014, 46, 551–557, doi:10.1038/ng.2968.
  38. Peters, J. The role of genomic imprinting in biology and disease: An expanding view. Rev. Genet. 2014, 15, 517–530, doi:10.1038/nrg3766.
  39. Plasschaert, R.N.; Bartolomei, M.S. Genomic imprinting in development, growth, behavior and stem cells. Development 2014, 141, 1805–1813, doi:10.1242/dev.101428.
  40. Monk, D. Deciphering the cancer imprintome. Briefings Funct. Genom. Proteom. 2010, 9, 329–339, doi:10.1093/bfgp/elq013.
  41. Zamarbide, M.; Gil-Bea, F.J.; Bannenberg, P.; Martínez-Pinilla, E.; Sandoval, J.; Franco, R.; Pérez-Mediavilla, A. Maternal imprinting on cognition markers of wild type and transgenic Alzheimer’s disease model mice. Rep. 2018, 8, doi:10.1038/s41598-018-24710-7.
  42. Wallace, C.; Smyth, D.J.; Maisuria-Armer, M.; Walker, N.M.; Todd, J.A.; Clayton, D.G. The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Genet. 2010, 42, 68–71, doi:10.1038/ng.493.
  43. Blunk, I.; Thomsen, H.; Reinsch, N.; Mayer, M.; Försti, A.; Sundquist, J.; Sundquist, K.; Hemminki, K. Genomic imprinting analyses identify maternal effects as a cause of phenotypic variability in type 1 diabetes and rheumatoid arthritis. Rep. 2020, 10, doi:10.1038/s41598-020-68212-x.
  44. Baulina, N.; Osmak, G.; Kiselev, I.; Popova, E.; Boyko, A.; Kulakova, O.; Favorova, O. MiRNAs from DLK1-DIO3 Imprinted Locus at 14q32 are Associated with Multiple Sclerosis: Gender-Specific Expression and Regulation of Receptor Tyrosine Kinases Signaling. Cells 2019, 8, 133, doi:10.3390/cells8020133.
  45. Ruhrmann, S.; Stridh, P.; Kular, L.; Jagodic, M. Genomic imprinting: A missing piece of the Multiple Sclerosis puzzle? J. Biochem. Cell Biol. 2015, 67, 49–57, doi:10.1016/j.biocel.2015.05.010.