Abstract
Epigenetic diseases can be produced by a stable alteration, called an epimutation, in DNA methylation, in which epigenome alterations are directly involved in the underlying molecular mechanisms of the disease. This review focuses on the epigenetics of two inherited metabolic diseases, epi-cblC, an inherited metabolic disorder of cobalamin (vitamin B12) metabolism, and alpha-thalassemia type α-ZF, an inherited disorder of α2-globin synthesis, with a particular interest in the role of aberrant antisense transcription of flanking genes in the generation of epimutations in CpG islands of gene promoters. In both disorders, the epimutation is triggered by an aberrant antisense transcription through the promoter, which produces an H3K36me3 histone mark involved in the recruitment of DNA methyltransferases. It results from diverse genetic alterations. In alpha-thalassemia type α-ZF, a deletion removes HBA1 and HBQ1 genes and juxtaposes the antisense LUC7L gene to the HBA2 gene. In epi-cblC, the epimutation in the MMACHC promoter is produced by mutations in the antisense flanking gene PRDX1, which induces a prolonged antisense transcription through the MMACHC promoter. The presence of the epimutation in sperm, its transgenerational inheritance via the mutated PRDX1, and the high expression of PRDX1 in spermatogonia but its nearly undetectable transcription in spermatids and spermatocytes, suggest that the epimutation could be maintained during germline reprogramming and despite removal of aberrant transcription. The epivariation seen in the MMACHC promoter (0.95 × 10–3) is highly frequent compared to epivariations affecting other genes of the Online Catalog of Human Genes and Genetic Disorders in an epigenome-wide dataset of 23,116 individuals. This and the comparison of epigrams of two monozygotic twins suggest that the aberrant transcription could also be influenced by post-zygotic environmental exposures.
Similar content being viewed by others
Availability of data and material
Data sharing does not apply to this article as no datasets were generated during the current study.
Code availability
Not applicable.
References
Ahmed W, Lingner J (2020) PRDX1 counteracts catastrophic telomeric cleavage events that are triggered by DNA repair activities post oxidative damage. Cell Rep 33:108347. https://doi.org/10.1016/j.celrep.2020.108347
Barbour VM, Tufarelli C, Sharpe JA, Smith ZE, Ayyub H, Heinlein CA, Sloane-Stanley J, Indrak K, Wood WG, Higgs DR (2000) alpha-thalassemia resulting from a negative chromosomal position effect. Blood 96:800–807
Barlow DP, Bartolomei MS (2014) Genomic imprinting in mammals. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a018382
Baubec T, Colombo DF, Wirbelauer C, Schmidt J, Burger L, Krebs AR, Akalin A, Schubeler D (2015) Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520:243–247. https://doi.org/10.1038/nature14176
Beygo J, Burger J, Strom TM, Kaya S, Buiting K (2019) Disruption of KCNQ1 prevents methylation of the ICR2 and supports the hypothesis that its transcription is necessary for imprint establishment. Eur J Hum Genet 27:903–908. https://doi.org/10.1038/s41431-019-0365-x
Bliek J, Maas SM, Ruijter JM, Hennekam RC, Alders M, Westerveld A, Mannens MM (2001) Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS. Hum Mol Genet 10:467–476. https://doi.org/10.1093/hmg/10.5.467
Brioude F, Hennekam R, Bliek J, Coze C, Eggermann T, Ferrero GB, Kratz C, Bouc YL, Maas SM, Mackay DJG, Maher ER, Mussa A, Netchine I (2018a) Revisiting Wilms tumour surveillance in Beckwith–Wiedemann syndrome with IC2 methylation loss, reply. Eur J Hum Genet 26:471–472. https://doi.org/10.1038/s41431-017-0074-2
Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, Boonen SE, Cole T, Baker R, Bertoletti M, Cocchi G, Coze C, De Pellegrin M, Hussain K, Ibrahim A, Kilby MD, Krajewska-Walasek M, Kratz CP, Ladusans EJ, Lapunzina P, Le Bouc Y, Maas SM, Macdonald F, Ounap K, Peruzzi L, Rossignol S, Russo S, Shipster C, Skorka A, Tatton-Brown K, Tenorio J, Tortora C, Gronskov K, Netchine I, Hennekam RC, Prawitt D, Tumer Z, Eggermann T, Mackay DJG, Riccio A, Maher ER (2018b) Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith–Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol 14:229–249. https://doi.org/10.1038/nrendo.2017.166
Cavicchi C, Oussalah A, Falliano S, Ferri L, Gozzini A, Gasperini S, Motta S, Rigoldi M, Parenti G, Tummolo A, Meli C, Menni F, Furlan F, Daniotti M, Malvagia S, la Marca G, Chery C, Morange PE, Tregouet D, Donati MA, Guerrini R, Gueant JL, Morrone A (2021) PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations. Clin Epigenetics 13:137. https://doi.org/10.1186/s13148-021-01117-2
Chang S, Bartolomei MS (2020) Modeling human epigenetic disorders in mice: Beckwith–Wiedemann syndrome and Silver–Russell syndrome. Dis Model Mech. https://doi.org/10.1242/dmm.044123
Chen Y, Yin D, Li L, Deng YC, Tian W (2015) Screening aberrant methylation profile in esophageal squamous cell carcinoma for Kazakhs in Xinjiang area of China. Mol Biol Rep 42:457–464. https://doi.org/10.1007/s11033-014-3788-z
Chotalia M, Smallwood SA, Ruf N, Dawson C, Lucifero D, Frontera M, James K, Dean W, Kelsey G (2009) Transcription is required for establishment of germline methylation marks at imprinted genes. Genes Dev 23:105–117. https://doi.org/10.1101/gad.495809
Chu G, Li J, Zhao Y, Liu N, Zhu X, Liu Q, Wei D, Gao C (2016) Identification and verification of PRDX1 as an inflammation marker for colorectal cancer progression. Am J Transl Res 8:842–859
Crampton N, Bonass WA, Kirkham J, Rivetti C, Thomson NH (2006) Collision events between RNA polymerases in convergent transcription studied by atomic force microscopy. Nucleic Acids Res 34:5416–5425. https://doi.org/10.1093/nar/gkl668
Cruvinel E, Budinetz T, Germain N, Chamberlain S, Lalande M, Martins-Taylor K (2014) Reactivation of maternal SNORD116 cluster via SETDB1 knockdown in Prader–Willi syndrome iPSCs. Hum Mol Genet 23:4674–4685. https://doi.org/10.1093/hmg/ddu187
DeBaun MR, King AA, White N (2000) Hypoglycemia in Beckwith–Wiedemann syndrome. Semin Perinatol 24:164–171. https://doi.org/10.1053/sp.2000.6366
Ding C, Fan X, Wu G (2017) Peroxiredoxin 1—an antioxidant enzyme in cancer. J Cell Mol Med 21:193–202. https://doi.org/10.1111/jcmm.12955
Duffy KA, Cielo CM, Cohen JL, Gonzalez-Gandolfi CX, Griff JR, Hathaway ER, Kupa J, Taylor JA, Wang KH, Ganguly A, Deardorff MA, Kalish JM (2019) Characterization of the Beckwith–Wiedemann spectrum: diagnosis and management. Am J Med Genet C Semin Med Genet 181:693–708. https://doi.org/10.1002/ajmg.c.31740
Edwards CA, Ferguson-Smith AC (2007) Mechanisms regulating imprinted genes in clusters. Curr Opin Cell Biol 19:281–289. https://doi.org/10.1016/j.ceb.2007.04.013
Edwards JR, Yarychkivska O, Boulard M, Bestor TH (2017) DNA methylation and DNA methyltransferases. Epigenet Chromatin 10:23. https://doi.org/10.1186/s13072-017-0130-8
Garg P, Jadhav B, Rodriguez OL, Patel N, Martin-Trujillo A, Jain M, Metsu S, Olsen H, Paten B, Ritz B, Kooy RF, Gecz J, Sharp AJ (2020) A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and CGG expansions. Am J Hum Genet 107:654–669. https://doi.org/10.1016/j.ajhg.2020.08.019
Green R, Allen LH, Bjorke-Monsen AL, Brito A, Gueant JL, Miller JW, Molloy AM, Nexo E, Stabler S, Toh BH, Ueland PM, Yajnik C (2017) Vitamin B12 deficiency. Nat Rev Dis Primers 3:17040. https://doi.org/10.1038/nrdp.2017.40
Guéant JL, Namour F, Guéant-Rodriguez RM, Daval JL (2013) Folate and fetal programming: a play in epigenomics? Trends Endocrinol Metab 24:279–289. https://doi.org/10.1016/j.tem.2013.01.010
Guéant JL, Chéry C, Oussalah A, Nadaf J, Coelho D, Josse T, Flayac J, Robert A, Koscinski I, Gastin I, Filhine-Tresarrieu P, Pupavac M, Brebner A, Watkins D, Pastinen T, Montpetit A, Hariri F, Tregouët D, Raby BA, Chung WK, Morange PE, Froese DS, Baumgartner MR, Benoist JF, Ficicioglu C, Marchand V, Motorin Y, Bonnemains C, Feillet F, Majewski J, Rosenblatt DS (2018) Publisher Correction: A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients. Nat Commun 9:554. https://doi.org/10.1038/s41467-018-03054-w
Heard E, Martienssen RA (2014) Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157:95–109. https://doi.org/10.1016/j.cell.2014.02.045
Hitchins MP (2016) Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation. Fam Cancer 15:413–422. https://doi.org/10.1007/s10689-016-9887-3
Hitchins MP, Wong JJ, Suthers G, Suter CM, Martin DI, Hawkins NJ, Ward RL (2007) Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med 356:697–705. https://doi.org/10.1056/NEJMoa064522
Hobson DJ, Wei W, Steinmetz LM, Svejstrup JQ (2012) RNA polymerase II collision interrupts convergent transcription. Mol Cell 48:365–374. https://doi.org/10.1016/j.molcel.2012.08.027
Horsthemke B (2006) Epimutations in human disease. Curr Top Microbiol Immunol 310:45–59. https://doi.org/10.1007/3-540-31181-5_4
Huemer M, Diodato D, Schwahn B, Schiff M, Bandeira A, Benoist JF, Burlina A, Cerone R, Couce ML, Garcia-Cazorla A, la Marca G, Pasquini E, Vilarinho L, Weisfeld-Adams JD, Kožich V, Blom H, Baumgartner MR, Dionisi-Vici C (2017) Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. J Inherit Metab Dis 40:21–48. https://doi.org/10.1007/s10545-016-9991-4
Jang HH, Lee KO, Chi YH, Jung BG, Park SK, Park JH, Lee JR, Lee SS, Moon JC, Yun JW, Choi YO, Kim WY, Kang JS, Cheong GW, Yun DJ, Rhee SG, Cho MJ, Lee SY (2004) Two enzymes in one; two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function. Cell 117:625–635. https://doi.org/10.1016/j.cell.2004.05.002
Jeziorska DM, Murray RJS, De Gobbi M, Gaentzsch R, Garrick D, Ayyub H, Chen T, Li E, Telenius J, Lynch M, Graham B, Smith AJH, Lund JN, Hughes JR, Higgs DR, Tufarelli C (2017) DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease. Proc Natl Acad Sci USA 114:E7526–E7535. https://doi.org/10.1073/pnas.1703087114
Joh K, Matsuhisa F, Kitajima S, Nishioka K, Higashimoto K, Yatsuki H, Kono T, Koseki H, Soejima H (2018) Growing oocyte-specific transcription-dependent de novo DNA methylation at the imprinted Zrsr1-DMR. Epigenet Chromatin 11:28. https://doi.org/10.1186/s13072-018-0200-6
Kelsey G, Feil R (2013) New insights into establishment and maintenance of DNA methylation imprints in mammals. Philos Trans R Soc Lond B Biol Sci 368:20110336. https://doi.org/10.1098/rstb.2011.0336
Kerbel RS, Man MS, Dexter D (1984) A model of human cancer metastasis: extensive spontaneous and artificial metastases of a human pigmented melanoma and derived variant sublines in nude mice. J Natl Cancer Inst 72:93–108. https://doi.org/10.1093/jnci/72.1.93
Khatiwala RV, Zhang S, Li X, Devejian N, Bennett E, Cai C (2018) Inhibition of p16(INK4A) to rejuvenate aging human cardiac progenitor cells via the upregulation of anti-oxidant and NFkappaB signal pathways. Stem Cell Rev Rep 14:612–625. https://doi.org/10.1007/s12015-018-9815-z
Kim SU, Park YH, Kim JM, Sun HN, Song IS, Huang SM, Lee SH, Chae JI, Hong S, Sik Choi S, Choi SC, Lee TH, Kang SW, Rhee SG, Chang KT, Lee SH, Yu DY, Lee DS (2014) Dominant role of peroxiredoxin/JNK axis in stemness regulation during neurogenesis from embryonic stem cells. Stem Cells 32:998–1011. https://doi.org/10.1002/stem.1593
Krogan NJ, Kim M, Tong A, Golshani A, Cagney G, Canadien V, Richards DP, Beattie BK, Emili A, Boone C, Shilatifard A, Buratowski S, Greenblatt J (2003) Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II. Mol Cell Biol 23:4207–4218. https://doi.org/10.1128/mcb.23.12.4207-4218.2003
Langouet M, Gorka D, Orniacki C, Dupont-Thibert CM, Chung MS, Glatt-Deeley HR, Germain N, Crandall LJ, Cotney JL, Stoddard CE, Lalande M, Chamberlain SJ (2020) Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader–Willi syndrome neurons. Hum Mol Genet 29:3285–3295. https://doi.org/10.1093/hmg/ddaa210
Lecerf C, Le Bourhis X, Adriaenssens E (2019) The long non-coding RNA H19: an active player with multiple facets to sustain the hallmarks of cancer. Cell Mol Life Sci 76:4673–4687. https://doi.org/10.1007/s00018-019-03240-z
Ledgerwood EC, Marshall JW, Weijman JF (2017) The role of peroxiredoxin 1 in redox sensing and transducing. Arch Biochem Biophys 617:60–67. https://doi.org/10.1016/j.abb.2016.10.009
Lee HJ, Hore TA, Reik W (2014) Reprogramming the methylome: erasing memory and creating diversity. Cell Stem Cell 14:710–719. https://doi.org/10.1016/j.stem.2014.05.008
Lees-Murdock DJ, Walsh CP (2008) DNA methylation reprogramming in the germ line. Epigenetics 3:5–13. https://doi.org/10.4161/epi.3.1.5553
Lees-Murdock DJ, Shovlin TC, Gardiner T, De Felici M, Walsh CP (2005) DNA methyltransferase expression in the mouse germ line during periods of de novo methylation. Dev Dyn 232:992–1002. https://doi.org/10.1002/dvdy.20288
Lewis MW, Brant JO, Kramer JM, Moss JI, Yang TP, Hansen PJ, Williams RS, Resnick JL (2015) Angelman syndrome imprinting center encodes a transcriptional promoter. Proc Natl Acad Sci USA 112:6871–6875. https://doi.org/10.1073/pnas.1411261111
Lewis MW, Vargas-Franco D, Morse DA, Resnick JL (2019) A mouse model of Angelman syndrome imprinting defects. Hum Mol Genet 28:220–229. https://doi.org/10.1093/hmg/ddy345
Li E, Beard C, Jaenisch R (1993) Role for DNA methylation in genomic imprinting. Nature 366:362–365. https://doi.org/10.1038/366362a0
Li B, Ishii T, Tan CP, Soh JW, Goff SP (2002) Pathways of induction of peroxiredoxin I expression in osteoblasts: roles of p38 mitogen-activated protein kinase and protein kinase C. J Biol Chem 277:12418–12422. https://doi.org/10.1074/jbc.M111443200
Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, Lee TY, Bodmer D, Hoenselaar E, Hendriks-Cornelissen SJ, Tsui WY, Kong CK, Brunner HG, van Kessel AG, Yuen ST, van Krieken JH, Leung SY, Hoogerbrugge N (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3’ exons of TACSTD1. Nat Genet 41:112–117. https://doi.org/10.1038/ng.283
Liteplo RG, Hipwell SE, Rosenblatt DS, Sillaots S, Lue-Shing H (1991) Changes in cobalamin metabolism are associated with altered methionine auxotrophy of highly growth autonomous human melanoma cells. J Cell Physiol 149:332–338. https://doi.org/10.1002/jcp.1041490222
Loewy AD, Niles KM, Anastasio N, Watkins D, Lavoie J, Lerner-Ellis JP, Pastinen T, Trasler JM, Rosenblatt DS (2009) Epigenetic modification of the gene for the vitamin B(12) chaperone MMACHC can result in increased tumorigenicity and methionine dependence. Mol Genet Metab 96:261–267. https://doi.org/10.1016/j.ymgme.2008.12.011
Loos F, Loda A, van Wijk L, Grootegoed JA, Gribnau J (2015) Chromatin-mediated reversible silencing of sense–antisense gene pairs in embryonic stem cells is consolidated upon differentiation. Mol Cell Biol 35:2436–2447. https://doi.org/10.1128/mcb.00029-15
Martin DI, Cropley JE, Suter CM (2011) Epigenetics in disease: leader or follower? Epigenetics 6:843–848. https://doi.org/10.4161/epi.6.7.16498
McCarrey JR (2015) EPIGENETICS. the epigenome—a family affair. Science 350:634–635. https://doi.org/10.1126/science.aad5138
Mendiola AJP, LaSalle JM (2021) Epigenetics in Prader–Willi syndrome. Front Genet 12:624581. https://doi.org/10.3389/fgene.2021.624581
Mu ZM, Yin XY, Prochownik EV (2002) Pag, a putative tumor suppressor, interacts with the Myc Box II domain of c-Myc and selectively alters its biological function and target gene expression. J Biol Chem 277:43175–43184. https://doi.org/10.1074/jbc.M206066200
Mussa A, Russo S, De Crescenzo A, Chiesa N, Molinatto C, Selicorni A, Richiardi L, Larizza L, Silengo MC, Riccio A, Ferrero GB (2013) Prevalence of Beckwith–Wiedemann syndrome in North West of Italy. Am J Med Genet A 161A:2481–2486. https://doi.org/10.1002/ajmg.a.36080
Nilsson EE, Skinner MK (2015) Environmentally induced epigenetic transgenerational inheritance of disease susceptibility. Transl Res 165:12–17. https://doi.org/10.1016/j.trsl.2014.02.003
Oey H, Whitelaw E (2014) On the meaning of the word “epimutation.” Trends Genet 30:519–520. https://doi.org/10.1016/j.tig.2014.08.005
O’Flaherty C, Boisvert A, Manku G, Culty M (2019) Protective role of peroxiredoxins against reactive oxygen species in neonatal rat testicular gonocytes. Antioxidants (basel). https://doi.org/10.3390/antiox9010032
O’Leary VB, Ovsepian SV, Carrascosa LG, Buske FA, Radulovic V, Niyazi M, Moertl S, Trau M, Atkinson MJ, Anastasov N (2015) PARTICLE, a triplex-forming long ncRNA, regulates locus-specific methylation in response to low-dose irradiation. Cell Rep 11:474–485. https://doi.org/10.1016/j.celrep.2015.03.043
Papatheodorou I, Moreno P, Manning J, Fuentes AM, George N, Fexova S, Fonseca NA, Füllgrabe A, Green M, Huang N, Huerta L, Iqbal H, Jianu M, Mohammed S, Zhao L, Jarnuczak AF, Jupp S, Marioni J, Meyer K, Petryszak R, Prada Medina CA, Talavera-López C, Teichmann S, Vizcaino JA, Brazma A (2020) Expression Atlas update: from tissues to single cells. Nucleic Acids Res 48:D77-d83. https://doi.org/10.1093/nar/gkz947
Plasschaert RN, Bartolomei MS (2014) Genomic imprinting in development, growth, behavior and stem cells. Development 141:1805–1813. https://doi.org/10.1242/dev.101428
Radford EJ, Ito M, Shi H, Corish JA, Yamazawa K, Isganaitis E, Seisenberger S, Hore TA, Reik W, Erkek S, Peters A, Patti ME, Ferguson-Smith AC (2014) In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345:1255903. https://doi.org/10.1126/science.1255903
Shau H, Gupta RK, Golub SH (1993) Identification of a natural killer enhancing factor (NKEF) from human erythroid cells. Cell Immunol 147:1–11. https://doi.org/10.1006/cimm.1993.1043
Shearwin KE, Callen BP, Egan JB (2005) Transcriptional interference—a crash course. Trends Genet 21:339–345. https://doi.org/10.1016/j.tig.2005.04.009
Siklenka K, Erkek S, Godmann M, Lambrot R, McGraw S, Lafleur C, Cohen T, Xia J, Suderman M, Hallett M, Trasler J, Peters AH, Kimmins S (2015) Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science 350:aab2006. https://doi.org/10.1126/science.aab2006
Singh P, Wu X, Lee DH, Li AX, Rauch TA, Pfeifer GP, Mann JR, Szabo PE (2011) Chromosome-wide analysis of parental allele-specific chromatin and DNA methylation. Mol Cell Biol 31:1757–1770. https://doi.org/10.1128/MCB.00961-10
Smith EY, Futtner CR, Chamberlain SJ, Johnstone KA, Resnick JL (2011) Transcription is required to establish maternal imprinting at the Prader–Willi syndrome and Angelman syndrome locus. PLoS Genet 7:e1002422. https://doi.org/10.1371/journal.pgen.1002422
Stouder C, Paoloni-Giacobino A (2011) Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes. Reproduction 141:207–216. https://doi.org/10.1530/rep-10-0400
Tufarelli C, Stanley JA, Garrick D, Sharpe JA, Ayyub H, Wood WG, Higgs DR (2003) Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat Genet 34:157–165. https://doi.org/10.1038/ng1157
Valente FM, Sparago A, Freschi A, Hill-Harfe K, Maas SM, Frints SGM, Alders M, Pignata L, Franzese M, Angelini C, Carli D, Mussa A, Gazzin A, Gabbarini F, Acurzio B, Ferrero GB, Bliek J, Williams CA, Riccio A, Cerrato F (2019) Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus. Genet Med 21:1808–1820. https://doi.org/10.1038/s41436-018-0416-7
Velasco G, Hube F, Rollin J, Neuillet D, Philippe C, Bouzinba-Segard H, Galvani A, Viegas-Pequignot E, Francastel C (2010) Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues. Proc Natl Acad Sci USA 107:9281–9286. https://doi.org/10.1073/pnas.1000473107
Veselovska L, Smallwood SA, Saadeh H, Stewart KR, Krueger F, Maupetit-Mehouas S, Arnaud P, Tomizawa S, Andrews S, Kelsey G (2015) Deep sequencing and de novo assembly of the mouse oocyte transcriptome define the contribution of transcription to the DNA methylation landscape. Genome Biol 16:209. https://doi.org/10.1186/s13059-015-0769-z
Vora N, Bianchi DW (2009) Genetic considerations in the prenatal diagnosis of overgrowth syndromes. Prenat Diagn 29:923–929. https://doi.org/10.1002/pd.2319
Walton EL, Francastel C, Velasco G (2011) Maintenance of DNA methylation: Dnmt3b joins the dance. Epigenetics 6:1373–1377. https://doi.org/10.4161/epi.6.11.17978
Watkins D, Rosenblatt DS (2016) Lessons in biology from patients with inherited disorders of vitamin B12 and folate metabolism. Biochimie 126:3–5. https://doi.org/10.1016/j.biochi.2016.05.001
Weksberg R, Shuman C, Beckwith JB (2010) Beckwith–Wiedemann syndrome. Eur J Hum Genet 18:8–14. https://doi.org/10.1038/ejhg.2009.106
Wen ST, Van Etten RA (1997) The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity. Genes Dev 11:2456–2467. https://doi.org/10.1101/gad.11.19.2456
Xin F, Susiarjo M, Bartolomei MS (2015) Multigenerational and transgenerational effects of endocrine disrupting chemicals: a role for altered epigenetic regulation? Semin Cell Dev Biol 43:66–75. https://doi.org/10.1016/j.semcdb.2015.05.008
Yarychkivska O, Shahabuddin Z, Comfort N, Boulard M, Bestor TH (2018) BAH domains and a histone-like motif in DNA methyltransferase 1 (DNMT1) regulate de novo and maintenance methylation in vivo. J Biol Chem 293:19466–19475. https://doi.org/10.1074/jbc.RA118.004612
Yoshimizu T, Miroglio A, Ripoche MA, Gabory A, Vernucci M, Riccio A, Colnot S, Godard C, Terris B, Jammes H, Dandolo L (2008) The H19 locus acts in vivo as a tumor suppressor. Proc Natl Acad Sci USA 105:12417–12422. https://doi.org/10.1073/pnas.0801540105
Zama AM, Uzumcu M (2009) Fetal and neonatal exposure to the endocrine disruptor methoxychlor causes epigenetic alterations in adult ovarian genes. Endocrinology 150:4681–4691. https://doi.org/10.1210/en.2009-0499
Zhang X, Chen Q, Song Y, Guo P, Wang Y, Luo S, Zhang Y, Zhou C, Li D, Chen Y, Wei H (2021) Epimutation of MMACHC compound to a genetic mutation in cblC cases. Mol Genet Genomic Med 9:e1625. https://doi.org/10.1002/mgg3.1625
Zhou H, Wang B, Yang YX, Jia QJ, Zhang A, Qi ZW, Zhang JP (2019) Long noncoding RNAs in pathological cardiac remodeling: a review of the update literature. Biomed Res Int 2019:7159592. https://doi.org/10.1155/2019/7159592
Funding
The study was funded by the research project FHU ARRIMAGE and the French PIA project GEENAGE of “Lorraine Université d’Excellence”, reference ANR-15-IDEX-04-LUE and the equipment of the genomic platform of UMRS1256 NGERE/UMS208 by the CPER IT2MP (Contrat Plan État Région, Innovations Technologiques, Modélisation and Médecine Personnalisée) and FEDER (Fonds européen de développement régional) (Grant number: ITM2P).
Author information
Authors and Affiliations
Contributions
Main drafting of the manuscript: JLG. Acquisition, analysis, or interpretation of data: JLG, AO, YS, RMG-R. Critical revision of the manuscript: all authors.
Corresponding author
Ethics declarations
Conflict of interest
The authors have no competing interests to declare.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Guéant, JL., Siblini, Y., Chéry, C. et al. Epimutation in inherited metabolic disorders: the influence of aberrant transcription in adjacent genes. Hum Genet 141, 1309–1325 (2022). https://doi.org/10.1007/s00439-021-02414-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-021-02414-9