Selenoproteins and Epigenetic Regulation in Mammals

  • Hsin-Yi Lu
  • Berna Somuncu
  • Jianhong Zhu
  • Meltem Muftuoglu
  • Wen-Hsing ChengEmail author
Reference work entry


Selenium is an essential mineral. There is a total of 25 mammalian selenoproteins that confer the majority of physiological and pathophysiological functions of selenium. All functionally characterized selenoproteins are oxidoreductases. In humans, extremely low levels of selenium in the body result in classic selenium deficiency diseases, and patients with mutations in genes involved in selenoprotein expression show selenoprotein deficiency and multisystem defects. Recent progress suggests important roles of certain selenoproteins in epigenetic regulation of promoter methylation, histone modifications, noncoding RNA expressions, and genome stability. Conversely, such epigenetic events can also influence selenoprotein expression. Understanding how selenoproteins function in epigenetic regulations will continue to offer positive impact on selenium regulation toward optimal health.


Selenium Selenocysteine Selenoproteins Mineral Nutrition Oxidative stress Genome maintenance CpG methylation Histone Noncoding RNA 

List of Abbreviations




Iodothyronine deiodinase


DNA methyltransferase


Glutathione peroxidase


Long intergenic noncoding RNA




Noncoding RNA


Piwi-interacting RNA


SECIS-binding protein 2


Selenocysteine insertion sequence




Selenophosphate synthetase-2


Selenocysteine synthase


Small interfering RNA


Thioredoxin reductase



This chapter was partially supported by the USDA National Institute of Food and Agriculture (Multistate NE1439, accession no. 1008124, project no. MIS-384050), the Scientific and Technological Research Council of Turkey (TUBITAK, grant no. 114Z875), Zhejiang Provincial Natural Science Foundation Distinguished Young Scholar Program (LR13H020002), and Wenzhou Science and Technology Bureau (Y20150005).


  1. Agamy O, Zeev BB, Lev D, Marcus B, Fine D, Su D, Narkis G, Ofir R, Hoffmann C, Leshinsky-Silver E (2010) Mutations disrupting selenocysteine formation cause progressive cerebello-cerebral atrophy. Am J Hum Genet 87:538–544CrossRefGoogle Scholar
  2. Anttonen A-K, Hilander T, Linnankivi T, Isohanni P, French RL, Liu Y, Simonović M, Söll D, Somer M, Muth-Pawlak D (2015) Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate. Neurology 85:306–315CrossRefGoogle Scholar
  3. Baliga MS, Diwadkar-Navsariwala V, Koh T, Fayad R, Fantuzzi G, Diamond AM (2008) Selenoprotein deficiency enhances radiation-induced micronuclei formation. Mol Nutr Food Res 52:1300–1304CrossRefGoogle Scholar
  4. Bansal MP, Oborn CJ, Danielson KG, Medina D (1989) Evidence for two selenium-binding proteins distinct from glutathione peroxidase in mouse liver. Carcinogenesis 10:541–546CrossRefGoogle Scholar
  5. Behne D, Hilmert H, Scheid S, Gessner H, Elger W (1988) Evidence for specific selenium target tissues and new biologically important selenoproteins. Biochim Biophys Acta 966:12–21CrossRefGoogle Scholar
  6. Bilsland AE, Revie J, Keith W (2013) MicroRNA and senescence: the senectome, integration and distributed control. Crit Rev Oncog 18:373–390CrossRefGoogle Scholar
  7. Boguslawska J, Wojcicka A, Piekielko-Witkowska A, Master A, Nauman A (2011) MiR-224 targets the 3′ UTR of type 1 5′-iodothyronine deiodinase possibly contributing to tissue hypothyroidism in renal cancer. PLoS One.
  8. Bosl MR, Takaku K, Oshima M, Nishimura S, Taketo MM (1997) Early embryonic lethality caused by targeted disruption of the mouse selenocysteine tRNA gene (Trsp). Proc Natl Acad Sci U S A 94:5531–5534CrossRefGoogle Scholar
  9. Bosse AC, Pallauf J, Hommel B, Sturm M, Fischer S, Wolf NM, Mueller AS (2010) Impact of selenite and selenate on differentially expressed genes in rat liver examined by microarray analysis. Biosci Rep 30:293–306CrossRefGoogle Scholar
  10. Budiman ME, Bubenik JL, Miniard AC, Middleton LM, Gerber CA, Cash A, Driscoll DM (2009) Eukaryotic initiation factor 4a3 is a selenium-regulated RNA-binding protein that selectively inhibits selenocysteine incorporation. Mol Cell 35:479–489CrossRefGoogle Scholar
  11. Burk RF, Christensen JM, Maguire MJ, Austin LM, Whetsell WO, May JM, Hill KE, Ebner FF (2006) A combined deficiency of vitamins E and C causes severe central nervous system damage in guinea pigs. J Nutr 136:1576–1581CrossRefGoogle Scholar
  12. Burk RF, Hill KE (2009) Selenoprotein P – expression, functions, and roles in mammals. Biochim Biophys Acta 1790:1441–1447CrossRefGoogle Scholar
  13. Burk RF, Hill KE, Motley AK (2001) Plasma selenium in specific and non-specific forms. Biofactors 14:107–114CrossRefGoogle Scholar
  14. Campisi J, di Fagagna FDA (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740CrossRefGoogle Scholar
  15. Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136:642–655CrossRefGoogle Scholar
  16. Chen L-L (2016) Linking long noncoding RNA localization and function. Trends Biochem Sci 41:761–772CrossRefGoogle Scholar
  17. Cheng W-H, Ho Y-S, Ross DA, Valentine BA, Combs GF, Lei XG (1997) Cellular glutathione peroxidase knockout mice express normal levels of selenium-dependent plasma and phospholipid hydroperoxide glutathione peroxidases in various tissues. J Nutr 127:1445–1450CrossRefGoogle Scholar
  18. Cheng W-H, Muftuoglu M, Wu RTY (2014) Selenium and epigenetic effects on histone marks and DNA methylation. In: Ho E, Domann F (eds) Nutrition and epigenetics. CRC Press, New York, pp 273–297CrossRefGoogle Scholar
  19. Collins LJ, Schönfeld B, Chen XS (2011) The epigenetics of non-coding RNA. In: Tollefsbol (ed) Handbook of epigenetics: the new molecular and medical genetics. Academic, Cambridge, pp 49–61CrossRefGoogle Scholar
  20. Combs F Jr (2015) Biomarkers of selenium status. Forum Nutr 7:2209–2236Google Scholar
  21. Combs GF, Watts JC, Jackson MI, Johnson LK, Zeng H, Scheett AJ, Uthus EO, Schomburg L, Hoeg A, Hoefig CS (2011) Determinants of selenium status in healthy adults. Nutr J.
  22. Curti V, Capelli E, Boschi F, Nabavi SF, Bongiorno AI, Habtemariam S, Nabavi SM, Daglia M (2014) Modulation of human miR-17–3p expression by methyl 3-O-methyl gallate as explanation of its in vivo protective activities. Mol Nutr Food Res 58:1776–1784CrossRefGoogle Scholar
  23. Dai R, Lu R, Ahmed SA (2016) The upregulation of genomic imprinted DLK1-Dio3 miRNAs in murine lupus is associated with global DNA hypomethylation. PLoS One.
  24. de Haan JB, Bladier C, Lotfi-Miri M, Taylor J, Hutchinson P, Crack PJ, Hertzog P, Kola I (2004) Fibroblasts derived from Gpx1 knockout mice display senescent-like features and are susceptible to H2O2-mediated cell death. Free Radic Biol Med 36:53–64CrossRefGoogle Scholar
  25. Dewing AST, Rueli RH, Robles MJ, Nguyen-Wu ED, Zeyda T, Berry MJ, Bellinger FP (2012) Expression and regulation of mouse selenoprotein P transcript variants differing in non-coding RNA. RNA Biol 9:1361–1369CrossRefGoogle Scholar
  26. di Fagagna FDA, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–198CrossRefGoogle Scholar
  27. Dominissini D, Nachtergaele S, Moshitch-Moshkovitz S, Peer E, Kol N, Ben-Haim MS, Dai Q, Di Segni A, Salmon-Divon M, Clark WC (2016) The dynamic N1-methyladenosine methylome in eukaryotic messenger RNA. Nature 530:441–446CrossRefGoogle Scholar
  28. Du J, Johnson LM, Jacobsen SE, Patel DJ (2015) DNA methylation pathways and their crosstalk with histone methylation. Nat Rev Mol Cell Biol 16:519–532CrossRefGoogle Scholar
  29. Fingerman IM, Zhang X, Ratzat W, Husain N, Cohen RF, Schuler GD (2013) NCBI epigenomics: what’s new for 2013. Nucleic Acids Res 41:D221–D225CrossRefGoogle Scholar
  30. Hill KE, Zhou J, Austin LM, Motley AK, Ham A-JL, Olson GE, Atkins JF, Gesteland RF, Burk RF (2007) The selenium-rich C-terminal domain of mouse selenoprotein P is necessary for the supply of selenium to brain and testis but not for the maintenance of whole body selenium. J Biol Chem 282:10972–10980CrossRefGoogle Scholar
  31. Janssen R, Zuidwijk MJ, Muller A, van Mil A, Dirkx E, Oudejans CBM, Paulus WJ, Simonides WS (2016) MicroRNA 214 is a potential regulator of thyroid hormone levels in the mouse heart following myocardial infarction, by targeting the thyroid-hormone-inactivating enzyme deiodinase type III. Front Endocrinol (Lausanne).
  32. Jerome-Morais A, Bera S, Rachidi W, Gann PH, Diamond AM (2013) The effects of selenium and the GPx-1 selenoprotein on the phosphorylation of H2AX. Biochim Biophys Acta 183D:3399–3406CrossRefGoogle Scholar
  33. Kim Y-C, Gerlitz G, Furusawa T, Catez F, Nussenzweig A, Oh K-S, Kraemer KH, Shiloh Y, Bustin M (2009) Activation of ATM depends on chromatin interactions occurring before induction of DNA damage. Nat Cell Biol 11:92–96CrossRefGoogle Scholar
  34. Kim BS, Jung JS, Jang JH, Kang KS, Kang SK (2011) Nuclear Argonaute 2 regulates adipose tissue-derived stem cell survival through direct control of miR10b and selenoprotein N1 expression. Aging Cell 10:277–291CrossRefGoogle Scholar
  35. Ku H-Y, Lin H (2014) PIWI proteins and their interactors in piRNA biogenesis, germline development and gene expression. Natl Sci Rev 1:205–218CrossRefGoogle Scholar
  36. Kulak MV, Cyr AR, Woodfield GW, Bogachek M, Spanheimer PM, Li T, Price DH, Domann FE, Weigel RJ (2013) Transcriptional regulation of the GPX1 gene by TFAP2C and aberrant CpG methylation in human breast cancer. Oncogene 32:4043–4051CrossRefGoogle Scholar
  37. Labunskyy VM, Hatfield DL, Gladyshev VN (2014) Selenoproteins: molecular pathways and physiological roles. Physiol Rev 94:739–777CrossRefGoogle Scholar
  38. Lei XG, Zhu J-H, Cheng W-H, Bao Y, Ho Y-S, Reddi AR, Holmgren A, Arnér ESJ (2016) Paradoxical roles of antioxidant enzymes: basic mechanisms and health implications. Physiol Rev 96:307–364CrossRefGoogle Scholar
  39. Lin H-C, Ho S-C, Chen Y-Y, Khoo K-H, Hsu P-H, Yen H-CS (2015) CRL2 aids elimination of truncated selenoproteins produced by failed UGA/sec decoding. Science 349:91–95CrossRefGoogle Scholar
  40. Luger K, Dechassa ML, Tremethick DJ (2012) New insights into nucleosome and chromatin structure: an ordered state or a disordered affair? Nat Rev Mol Cell Biol 13:436–447CrossRefGoogle Scholar
  41. MacFarlane L-A, R Murphy P. (2010) MicroRNA: biogenesis, function and role in cancer. Curr Genomics 11:537–561CrossRefGoogle Scholar
  42. Maciel-Dominguez A, Swan D, Ford D, Hesketh J (2013) Selenium alters miRNA profile in an intestinal cell line: evidence that miR-185 regulates expression of GPX2 and SEPSH2. Mol Nutr Food Res 57:2195–2205CrossRefGoogle Scholar
  43. Min SY, Kim HS, Jung EJ, Jung EJ, Do Jee C, Kim WH (2012) Prognostic significance of glutathione peroxidase 1 (GPX1) down-regulation and correlation with aberrant promoter methylation in human gastric cancer. Anticancer Res 32:3169–3175PubMedGoogle Scholar
  44. Miniard AC, Middleton LM, Budiman ME, Gerber CA, Driscoll DM (2010) Nucleolin binds to a subset of selenoprotein mRNAs and regulates their expression. Nucleic Acids Res 38:4807–4820CrossRefGoogle Scholar
  45. Moustafa ME, Carlson BA, El-Saadani MA, Kryukov GV, Sun Q-A, Harney JW, Hill KE, Combs GF, Feigenbaum L, Mansur DB (2001) Selective inhibition of selenocysteine tRNA maturation and selenoprotein synthesis in transgenic mice expressing isopentenyladenosine-deficient selenocysteine tRNA. Mol Cell Biol 21:3840–3852CrossRefGoogle Scholar
  46. Narayan V, Ravindra KC, Liao C, Kaushal N, Carlson BA, Prabhu KS (2015) Epigenetic regulation of inflammatory gene expression in macrophages by selenium. J Nutr Biochem 26:138–145CrossRefGoogle Scholar
  47. Olson GE, Winfrey VP, Hill KE, Burk RF (2008) Megalin mediates selenoprotein P uptake by kidney proximal tubule epithelial cells. J Biol Chem 283:6854–6860CrossRefGoogle Scholar
  48. Olson GE, Winfrey VP, NagDas SK, Hill KE, Burk RF (2007) Apolipoprotein E receptor-2 (ApoER2) mediates selenium uptake from selenoprotein P by the mouse testis. J Biol Chem 282:12290–12297CrossRefGoogle Scholar
  49. Pitts MW, Kremer PM, Hashimoto AC, Torres DJ, Byrns CN, Williams CS, Berry MJ (2015) Competition between the brain and testes under selenium-compromised conditions: insight into sex differences in selenium metabolism and risk of neurodevelopmental disease. J Neurosci 35:15326–15338CrossRefGoogle Scholar
  50. Potenza N, Castiello F, Panella M, Colonna G, Ciliberto G, Russo A, Costantini S (2016) Human MiR-544a modulates SELK expression in hepatocarcinoma cell lines. PLoS One.
  51. Schoenmakers E, Agostini M, Mitchell C, Schoenmakers N, Papp L, Rajanayagam O, Padidela R, Ceron-Gutierrez L, Doffinger R, Prevosto C (2010) Mutations in the selenocysteine insertion sequence–binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans. J Clin Invest 120:4220–4235CrossRefGoogle Scholar
  52. Schoenmakers E, Carlson B, Agostini M, Moran C, Rajanayagam O, Bochukova E, Tobe R, Peat R, Gevers E, Muntoni F (2016) Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis. J Clin Invest 126:992–996CrossRefGoogle Scholar
  53. Schomburg L, Schweizer U, Holtmann B, Flohé L, Sendtner M, Köhrle J (2003) Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochem J 370:397–402CrossRefGoogle Scholar
  54. Seyedali A, Berry MJ (2014) Nonsense-mediated decay factors are involved in the regulation of selenoprotein mRNA levels during selenium deficiency. RNA 20:1248–1256CrossRefGoogle Scholar
  55. Speckmann B, Grune T (2015) Epigenetic effects of selenium and their implications for health. Epigenetics 10:179–190CrossRefGoogle Scholar
  56. Squires JE, Davy P, Berry MJ, Allsopp R (2009) Attenuated expression of SECIS binding protein 2 causes loss of telomeric reserve without affecting telomerase. Exp Gerontol 44:619–623CrossRefGoogle Scholar
  57. Sunde RA, Raines AM (2011) Selenium regulation of the selenoprotein and nonselenoprotein transcriptomes in rodents. Adv Nutr 2:138–150CrossRefGoogle Scholar
  58. Tian B, Maidana DE, Dib B, Miller JB, Bouzika P, Miller JW, Vavvas DG, Lin H (2016) miR-17-3p exacerbates oxidative damage in human retinal pigment epithelial cells. PLoS One.
  59. Torres IO, Fujimori DG (2015) Functional coupling between writers, erasers and readers of histone and DNA methylation. Curr Opin Struct Biol 35:68–75CrossRefGoogle Scholar
  60. Vendeland SC, Butler JA, Whanger PD (1992) Intestinal absorption of selenite, selenate, and selenomethionine in the rat. J Nutr Biochem 3:359–365CrossRefGoogle Scholar
  61. Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43:904–914CrossRefGoogle Scholar
  62. Wang L, Huang H, Fan Y, Kong B, Hu H, Hu K, Guo J, Mei Y, Liu W-L (2014) Effects of downregulation of microRNA-181a on H2O2-induced H9c2 cell apoptosis via the mitochondrial apoptotic pathway. Oxidative Med Cell Longev.
  63. Wang XD, Vatamaniuk MZ, Wang SK, Roneker CA, Simmons RA, Lei XG (2008) Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice. Diabetologia 51:1515–1524CrossRefGoogle Scholar
  64. Wu RT, Cao L, Chen BPC, Cheng W-H (2014) Selenoprotein H suppresses cellular senescence through genome maintenance and redox regulation. J Biol Chem 289:34378–34388CrossRefGoogle Scholar
  65. Wu RT, Cao L, Mattson E, Witwer KW, Cao J, Zeng H, He X, Combs GF, Cheng WH (2017) Opposing impacts on healthspan and longevity by limiting dietary selenium in telomere dysfunctional mice. Aging Cell 16:125–135CrossRefGoogle Scholar
  66. Xu Y, Fang F, Zhang J, Josson S, Clair WHS, Clair DKS (2010) miR-17* suppresses tumorigenicity of prostate cancer by inhibiting mitochondrial antioxidant enzymes. PLoS One.
  67. Zhang Y, He Q, Hu Z, Feng Y, Fan L, Tang Z, Yuan J, Shan W, Li C, Hu X (2016b) Long noncoding RNA LINP1 regulates repair of DNA double-strand breaks in triple-negative breast cancer. Nat Struct Mol Biol 23:522–530CrossRefGoogle Scholar
  68. Zhang X, Zhang L, Zhu JH, Cheng WH (2016a) Nuclear selenoproteins and genome maintenance. IUBMB Life 68:5–12CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Hsin-Yi Lu
    • 1
  • Berna Somuncu
    • 2
  • Jianhong Zhu
    • 3
  • Meltem Muftuoglu
    • 2
  • Wen-Hsing Cheng
    • 1
    Email author
  1. 1.Department of Food Science, Nutrition and Health PromotionMississippi State UniversityMississippi StateUSA
  2. 2.Department of Molecular Biology and GeneticsAcibadem UniversityIstanbulTurkey
  3. 3.Department of Preventive Medicine, Department of Geriatrics and Neurology at the Second Affiliated Hospital, and Key Laboratory of Watershed Science and Health of Zhejiang ProvinceWenzhou Medical UniversityWenzhouChina

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