БИОХИМИЯ, 2022, том 87, вып. 9, с. 1301–1317

УДК 576.315.42

Сегрегация кластеров α‑ и β‑глобиновых генов в ходе эволюции позвоночных – случайность или закономерность?

Обзор

© 2022 О.В. Яровая 1*iarovaia@inbox.ru, С.В. Ульянов 1,2, Е.С. Юдинкова 1, С.В. Разин 1,2

Институт биологии гена РАН, 119334 Москва, Россия

Московский государственный университет имени М.В. Ломоносова, биологический факультет, 119234 Москва, Россия

Поступила в редакцию 22.07.2022
После доработки 18.08.2022
Принята к публикации 19.08.2022

DOI: 10.31857/S0320972522090093

КЛЮЧЕВЫЕ СЛОВА: эволюция α‑ и β‑глобиновых генов, регуляция транскрипции, неканонические функции α‑ и β‑глобинов.

Аннотация

Обзор посвящен закономерностям эволюции доменов α‑ и β‑глобиновых генов. Впервые представлена гипотеза, в соответствии с которой сегрегация предкового кластера α/β‑глобиновых генов Amniota закономерна и обусловлена выполнением α‑глобинами и β‑глобинами неканонических функций, не связанных с транспортом кислорода.

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Финансирование

Работа С.В. Разина поддержана Российским научным фондом (грант № 21-64-00001). Работа О.В. Яровой поддержана Российским фондом фундаментальных исследований (грант № 20-04-00003).

Вклад авторов

Все авторы участвовали в выработке концепции и написании обзора.

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит описания каких-либо исследований с участием людей или животных в качестве объектов.

Список литературы

1. De Simone, G., Quattrocchi, A., Mancini, B., di Masi, A., Nervi, C., et al. (2022) Thalassemias: from gene to therapy, Mol. Aspects Med., 84, 101028, doi: 10.1016/j.mam.2021.101028.

2. Fromm, G., and Bulger, M. (2009) A spectrum of gene regulatory phenomena at mammalian beta-globin gene loci, Biochem. Cell Biol., 87, 781-790, doi: 10.1139/O09-048.

3. Hardison, R. C. (2012) Evolution of hemoglobin and its genes, Cold Spring Harb. Perspect.Med., 2, a011627, doi: 10.1101/cshperspect.a011627.

4. Hoffmann, F. G., Vandewege, M. W., Storz, J. F., and Opazo, J. C. (2018) Gene turnover and diversification of the alpha- and beta-globin gene families in sauropsid vertebrates, Genome Biol. Evol., 10, 344-358, doi: 10.1093/gbe/evy001.

5. Iarovaia, O. V., Ioudinkova, E. S., Petrova, N. V., Dolgushin, K. V., Kovina, A. V., et al. (2014) Evolution of alpha- and beta-globin genes and their regulatory systems in light of the hypothesis of domain organization of the genome, Biochemistry (Moscow), 79, 1141-1150, doi: 10.1134/S0006297914110017.

6. Kattamis, A., Kwiatkowski, J. L., and Aydinok, Y. (2022) Thalassaemia, Lancet, 399, 2310-2324, doi: 10.1016/S0140-6736(22)00536-0.

7. Mettananda, S., Gibbons, R. J., and Higgs, D. R. (2016) Understanding alpha-globin gene regulation and implications for the treatment of beta-thalassemia, Ann. NY Acad. Sci., 1368, 16-24, doi: 10.1111/nyas.12988.

8. Oudelaar, A. M., Beagrie, R. A., Kassouf, M. T., and Higgs, D. R. (2021) The mouse alpha-globin cluster: a paradigm for studying genome regulation and organization, Curr. Opin. Genet. Dev., 67, 18-24, doi: 10.1016/j.gde.2020.10.003.

9. Philipsen, S., and Hardison, R. C. (2018) Evolution of hemoglobin loci and their regulatory elements, Blood Cells Mol. Diseases, 70, 2-12, doi: 10.1016/j.bcmd.2017.08.001.

10. Razin, S. V., Ulianov, S. V., Ioudinkova, E. S., Gushchanskaya, E. S., Gavrilov, A. A., et al. (2012) Domains of alpha- and beta-globin genes in the context of the structural-functional organization of the eukaryotic genome, Biochemistry (Moscow), 77, 1409-1423, doi: 10.1134/S0006297912130019.

11. Recillas-Targa, F., and Razin, S. V. (2001) Chromatin domains and regulation of gene expression: familiar and enigmatic clusters of chicken globin genes, Crit. Rev. Eukaryot. Gene Express., 11, 227-242.

12. Hardison, R. C. (2008) Globin genes on the move, J. Biol., 7, 35, doi: 10.1186/jbiol92.

13. Vinogradov, S. N., and Moens, L. (2008) Diversity of globin function: enzymatic, transport, storage, and sensing, J. Biol. Chem., 283, 8773-8777, doi: 10.1074/jbc.R700029200.

14. Burmester, T., and Hankeln, T. (2014) Function and evolution of vertebrate globins, Acta Physiol., 211, 501-514, doi: 10.1111/apha.12312.

15. Keppner, A., Maric, D., Correia, M., Koay, T. W., Orlando, I. M. C., et al. (2020) Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport, Redox Biol., 37, 101687, doi: 10.1016/j.redox.2020.101687.

16. Song, S., Starunov, V., Bailly, X., Ruta, C., Kerner, P., et al. (2020) Globins in the marine annelid Platynereis dumerilii shed new light on hemoglobin evolution in bilaterians, BMC Evol. Biol., 20, 165, doi: 10.1186/s12862-020-01714-4.

17. Hoffmann, F. G., Opazo, J. C., and Storz, J. F. (2012) Whole-genome duplications spurred the functional diversification of the globin gene superfamily in vertebrates, Mol. Biol. Evol., 29, 303-312, doi: 10.1093/molbev/msr207.

18. Miyata, M., Gillemans, N., Hockman, D., Demmers, J. A. A., Cheng, J. F., et al. (2020) An evolutionarily ancient mechanism for regulation of hemoglobin expression in vertebrate red cells, Blood, 136, 269-278, doi: 10.1182/blood.2020004826.

19. Storz, J. F., Opazo, J. C., and Hoffmann, F. G. (2013) Gene duplication, genome duplication, and the functional diversification of vertebrate globins, Mol. Phylogenet. Evol., 66, 469-478, doi: 10.1016/j.ympev.2012.07.013.

20. Pelleg, A., and Porter, R. S. (1990) The pharmacology of adenosine, Pharmacotherapy, 10, 157-174.

21. Pillai, A. S., Chandler, S. A., Liu, Y., Signore, A. V., Cortez-Romero, C. R., et al. (2020) Origin of complexity in haemoglobin evolution, Nature, 581, 480-485, doi: 10.1038/s41586-020-2292-y.

22. Weber, R. E., and Fago, A. (2004) Functional adaptation and its molecular basis in vertebrate hemoglobins, neuroglobins and cytoglobins, Respirat. Physiol. Neurobiol., 144, 141-159, doi: 10.1016/j.resp.2004.04.018.

23. Ganis, J. J., Hsia, N., Trompouki, E., de Jong, J. L., DiBiase, A., et al. (2012) Zebrafish globin switching occurs in two developmental stages and is controlled by the LCR, Dev. Biol., 366, 185-194, doi: 10.1016/j.ydbio.2012.03.021.

24. Nefedochkina, A. V., Petrova, N. V., Ioudinkova, E. S., Kovina, A. P., Iarovaia, O. V., et al. (2016) Characterization of the enhancer element of the Danio rerio minor globin gene locus, Histochem. Cell Biol., 145, 463-473, doi: 10.1007/s00418-016-1413-z.

25. Hosbach, H. A., Wyler, T., and Weber, R. (1983) The Xenopus laevis globin gene family: chromosomal arrangement and gene structure, Cell, 32, 45-53, doi: 10.1016/0092-8674(83)90495-6.

26. Jeffreys, A. J., Wilson, V., Wood, D., Simons, J. P., Kay, R. M., et al. (1980) Linkage of adult alpha- and beta-globin genes in X. laevis and gene duplication by tetraploidization, Cell, 21, 555-564, doi: 10.1016/0092-8674(80)90493-6.

27. Queiroz, J. P. F., Lima, N. C. B., and Rocha, B. A. M. (2021) The rise and fall of globins in the amphibia, Compar. Biochem. Physiol. D Genom. Proteom., 37, 100759, doi: 10.1016/j.cbd.2020.100759.

28. Fuchs, C., Burmester, T., and Hankeln, T. (2006) The amphibian globin gene repertoire as revealed by the Xenopus genome, Cytogenet. Genome Res., 112, 296-306, doi: 10.1159/000089884.

29. Patel, V. S., Cooper, S. J., Deakin, J. E., Fulton, B., Graves, T., et al. (2008) Platypus globin genes and flanking loci suggest a new insertional model for beta-globin evolution in birds and mammals, BMC Biol., 6, 34, doi: 10.1186/1741-7007-6-34.

30. Hughes, J. R., Cheng, J. F., Ventress, N., Prabhakar, S., Clark, K., et al. (2005) Annotation of cis-regulatory elements by identification, subclassification, and functional assessment of multispecies conserved sequences, Proc. Natl. Acad. Sci. USA, 102, 9830-9835, doi: 10.1073/pnas.0503401102.

31. Filonenko, E. S., Gavrilov, A. A., Razin, S. V., and Iarovaia, O. V. (2010) Expansion of the functional domain of chicken alpha-globin genes [in Russian], Genetika, 46, 1164-1167.

32. Philonenko, E. S., Klochkov, D. B., Borunova, V. V., Gavrilov, A. A., Razin, S. V., et al. (2009) TMEM8 — a non-globin gene entrapped in the globin web, Nucleic Acids Res., 37, 7394-7406, doi: 10.1093/nar/gkp838.

33. De Leo, A. A., Wheeler, D., Lefevre, C., Cheng, J. F., Hope, R., et al. (2005) Sequencing and mapping hemoglobin gene clusters in the Australian model dasyurid marsupial Sminthopsis macroura, Cytogenet. Genome Res., 108, 333-341, doi: 10.1159/000081528.

34. Opazo, J. C., Hoffmann, F. G., and Storz, J. F. (2008) Genomic evidence for independent origins of beta-like globin genes in monotremes and therian mammals, Proc. Natl. Acad. Sci. USA, 105, 1590-1595, doi: 10.1073/pnas.0710531105.

35. Wheeler, D., Hope, R. M., Cooper, S. J., Gooley, A. A., and Holland, R. A. (2004) Linkage of the beta-like omega-globin gene to alpha-like globin genes in an Australian marsupial supports the chromosome duplication model for separation of globin gene clusters, J. Mol. Evol., 58, 642-652, doi: 10.1007/s00239-004-2584-0.

36. Bulger, M., van Doorninck, J. H., Saitoh, N., Telling, A., Farrell, C., et al. (1999) Conservation of sequence and structure flanking the mouse and human beta-globin loci: the beta-globin genes are embedded within an array of odorant receptor genes, Proc. Natl. Acad. Sci. USA, 96, 5129-5134, doi: 10.1073/pnas.96.9.5129.

37. Palstra, R. J., de Laat, W., and Grosveld, F. (2008) Beta-globin regulation and long-range interactions, Adv. Genetics, 61, 107-142, doi: 10.1016/S0065-2660(07)00004-1.

38. Kovina, A. P., Petrova, N. V., Gushchanskaya, E. S., Dolgushin, K. V., Gerasimov, E. S., et al. (2017) Evolution of the genome 3D organization: comparison of fused and segregated globin gene clusters, Mol. Biol. Evol., 34, 1492-1504, doi: 10.1093/molbev/msx100.

39. Hay, D., Hughes, J. R., Babbs, C., Davies, J. O. J., Graham, B. J., et al. (2016) Genetic dissection of the alpha-globin super-enhancer in vivo, Nat. Genet., 48, 895-903, doi: 10.1038/ng.3605.

40. Garcia-Gonzalez, E., and Recillas-Targa, F. (2014) A regulatory element affects the activity and chromatin structure of the chicken alpha-globin 3′ enhancer, Biochim. Biophys. Acta, 1839, 1233-1241, doi: 10.1016/j.bbagrm.2014.09.009.

41. Bulger, M., Bender, M. A., van Doorninck, J. H., Wertman, B., Farrell, C. M., et al. (2000) Comparative structural and functional analysis of the olfactory receptor genes flanking the human and mouse beta-globin gene clusters, Proc. Natl. Acad. Sci. USA, 97, 14560-14565, doi: 10.1073/pnas.97.26.14560.

42. Bulger, M., and Groudine, M. (1999) Looping versus linking: toward a model for long-distance gene activation, Genes Dev., 13, 2465-2477, doi: 10.1101/gad.13.19.2465.

43. Levings, P. P., and Bungert, J. (2002) The human beta-globin locus control region, Eur. J. Biochem., 269, 1589-1599, doi: 10.1046/j.1432-1327.2002.02797.x.

44. Li, Q., Peterson, K. R., Fang, X., and Stamatoyannopoulos, G. (2002) Locus control regions, Blood, 100, 3077-3086, doi: 10.1182/blood-2002-04-1104.

45. Choi, O. R., and Engel, J. D. (1986) A 3′ enhancer is required for temporal and tissue-specific transcriptional activation of the chicken adult beta-globin gene, Nature, 323, 731-734, doi: 10.1038/323731a0.

46. Chung, J. H., Bell, A. C., and Felsenfeld, G. (1997) Characterization of the chicken beta-globin insulator, Proc. Natl. Acad. Sci. USA, 94, 575-580, doi: 10.1073/pnas.94.2.575.

47. Rival-Gervier, S., Pantano, T., Viglietta, C., Maeder, C., Prince, S., et al. (2003) The insulator effect of the 5′HS4 region from the beta-globin chicken locus on the rabbit WAP gene promoter activity in transgenic mice, Transgenic Res., 12, 723-730, doi: 10.1023/b:trag.0000005242.72076.d1.

48. Wallace, J. A., and Felsenfeld, G. (2007) We gather together: insulators and genome organization, Curr. Opin. Genet. Dev., 17, 400-407, doi: 10.1016/j.gde.2007.08.005.

49. De Laat, W., and Grosveld, F. (2003) Spatial organization of gene expression: the active chromatin hub, Chromosome Research: An International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology, 11, 447-459, doi: 10.1023/a:1024922626726.

50. Oudelaar, A. M., Harrold, C. L., Hanssen, L. L. P., Telenius, J. M., Higgs, D. R., et al. (2019) A revised model for promoter competition based on multi-way chromatin interactions at the alpha-globin locus, Nat. Commun., 10, 5412, doi: 10.1038/s41467-019-13404-x.

51. Vernimmen, D., Marques-Kranc, F., Sharpe, J. A., Sloane-Stanley, J. A., Wood, W. G., et al. (2009) Chromosome looping at the human alpha-globin locus is mediated via the major upstream regulatory element (HS-40), Blood, 114, 4253-4260, doi: 10.1182/blood-2009-03-213439.

52. Saha, D., Patgaonkar, M., Shroff, A., Ayyar, K., Bashir, T., et al. (2014) Hemoglobin expression in nonerythroid cells: novel or ubiquitous? Int. J. Inflamm., 2014, 803237, doi: 10.1155/2014/803237.

53. Russo, R., Zucchelli, S., Codrich, M., Marcuzzi, F., Verde, C., and Gustincich, S. (2013) Hemoglobin is present as a canonical alpha2beta2 tetramer in dopaminergic neurons, Biochim. Biophys. Acta, 1834, 1939-1943, doi: 10.1016/j.bbapap.2013.05.005.

54. Tezel, T. H., Geng, L., Lato, E. B., Schaal, S., Liu, Y., et al. (2009) Synthesis and secretion of hemoglobin by retinal pigment epithelium, Invest. Ophthalmol. Vis. Sci., 50, 1911-1919, doi: 10.1167/iovs.07-1372.

55. Wu, C. W., Liao, P. C., Yu, L., Wang, S. T., Chen, S. T., et al. (2004) Hemoglobin promotes Abeta oligomer formation and localizes in neurons and amyloid deposits, Neurobiol. Disease, 17, 367-377, doi: 10.1016/j.nbd.2004.08.014.

56. Biagioli, M., Pinto, M., Cesselli, D., Zaninello, M., Lazarevic, D., et al. (2009) Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells, Proc. Natl. Acad. Sci. USA, 106, 15454-15459, doi: 10.1073/pnas.0813216106.

57. Schelshorn, D. W., Schneider, A., Kuschinsky, W., Weber, D., Kruger, C., et al. (2009) Expression of hemoglobin in rodent neurons, J. Cereb. Blood Flow Metab., 29, 585-595, doi: 10.1038/jcbfm.2008.152.

58. Richter, F., Meurers, B. H., Zhu, C., Medvedeva, V. P., and Chesselet, M. F. (2009) Neurons express hemoglobin alpha- and beta-chains in rat and human brains, J. Compar. Neurol., 515, 538-547, doi: 10.1002/cne.22062.

59. Dassen, H., Kamps, R., Punyadeera, C., Dijcks, F., de Goeij, A., et al. (2008) Haemoglobin expression in human endometrium, Hum. Reprod., 23, 635-641, doi: 10.1093/humrep/dem430.

60. Babalola, O. E., Danboyi, P., and Abiose, A. A. (2000) Hereditary congenital cataracts associated with sickle cell anaemia in a Nigerian family, Tropic. Doc., 30, 12-14, doi: 10.1177/004947550003000107.

61. Wride, M. A., Mansergh, F. C., Adams, S., Everitt, R., Minnema, S. E., et al. (2003) Expression profiling and gene discovery in the mouse lens, Mol. Vis., 9, 360-396.

62. Alayash, A. I., Patel, R. P., and Cashon, R. E. (2001) Redox reactions of hemoglobin and myoglobin: biological and toxicological implications, Antioxid. Redox Signal., 3, 313-327, doi: 10.1089/152308601300185250.

63. Goldstein, S., and Samuni, A. (2005) Intra- and intermolecular oxidation of oxymyoglobin and oxyhemoglobin induced by hydroxyl and carbonate radicals, Free Radic. Biol. Med., 39, 511-519, doi: 10.1016/j.freeradbiomed.2005.04.003.

64. Masuoka, N., Kodama, H., Abe, T., Wang, D. H., and Nakano, T. (2003) Characterization of hydrogen peroxide removal reaction by hemoglobin in the presence of reduced pyridine nucleotides, Biochim. Biophys. Acta, 1637, 46-54, doi: 10.1016/s0925-4439(02)00213-2.

65. Reeder, B. J. (2017) Redox and peroxidase activities of the hemoglobin superfamily: relevance to health and disease, Antioxid. Redox Signal., 26, 763-776, doi: 10.1089/ars.2016.6803.

66. Franco, R., Navarro, G., and Martinez-Pinilla, E. (2019) Antioxidant defense mechanisms in erythrocytes and in the central nervous system, Antioxidants, 8, doi: 10.3390/antiox8020046.

67. Liu, W., Baker, S. S., Baker, R. D., Nowak, N. J., and Zhu, L. (2011) Upregulation of hemoglobin expression by oxidative stress in hepatocytes and its implication in nonalcoholic steatohepatitis, PLoS One, 6, e24363, doi: 10.1371/journal.pone.0024363.

68. Nishi, H., Inagi, R., Kato, H., Tanemoto, M., Kojima, I., et al. (2008) Hemoglobin is expressed by mesangial cells and reduces oxidant stress, J. Am. Soc. Nephrol., 19, 1500-1508, doi: 10.1681/ASN.2007101085.

69. Brown, N., Alkhayer, K., Clements, R., Singhal, N., Gregory, R., et al. (2016) Neuronal hemoglobin expression and its relevance to multiple sclerosis neuropathology, J. Mol. Neurosci., 59, 1-17, doi: 10.1007/s12031-015-0711-6.

70. Codrich, M., Bertuzzi, M., Russo, R., Francescatto, M., Espinoza, S., et al. (2017) Neuronal hemoglobin affects dopaminergic cells’ response to stress, Cell Death Disease, 8, e2538, doi: 10.1038/cddis.2016.458.

71. Shephard, F., Greville-Heygate, O., Marsh, O., Anderson, S., and Chakrabarti, L. (2014) A mitochondrial location for haemoglobins – dynamic distribution in ageing and Parkinson’s disease, Mitochondrion, 14, 64-72, doi: 10.1016/j.mito.2013.12.001.

72. Shirai, T., Imori, H., Konomi, G., Ikuta, T., Minoda, H., et al. (1989) Trace elements in patients on chronic hemodialysis. 1. Plasma aluminium, Fukuoka Shika Daigaku Gakkai zasshi, 16, 1-10.

73. Bhaskaran, M., Chen, H., Chen, Z., and Liu, L. (2005) Hemoglobin is expressed in alveolar epithelial type II cells, Biochem. Biophys. Res. Commun., 333, 1348-1352, doi: 10.1016/j.bbrc.2005.06.042.

74. Newton, D. A., Rao, K. M., Dluhy, R. A., and Baatz, J. E. (2006) Hemoglobin is expressed by alveolar epithelial cells, J. Biol. Chem., 281, 5668-5676, doi: 10.1074/jbc.M509314200.

75. Grek, C. L., Newton, D. A., Spyropoulos, D. D., and Baatz, J. E. (2011) Hypoxia up-regulates expression of hemoglobin in alveolar epithelial cells, Am. J. Respirat. Cell Mol. Biol., 44, 439-447, doi: 10.1165/rcmb.2009-0307OC.

76. Emara, M., Turner, A. R., and Allalunis-Turner, J. (2014) Adult, embryonic and fetal hemoglobin are expressed in human glioblastoma cells, Int. J. Oncol., 44, 514-520, doi: 10.3892/ijo.2013.2186.

77. Funnell, A. P., Vernimmen, D., Lim, W. F., Mak, K. S., Wienert, B., et al. (2014) Differential regulation of the alpha-globin locus by Kruppel-like Factor 3 in erythroid and non-erythroid cells, BMC Mol. Biol., 15, 8, doi: 10.1186/1471-2199-15-8.

78. Gorr, T. A., Wichmann, D., Pilarsky, C., Theurillat, J. P., Fabrizius, A., et al. (2011) Old proteins — new locations: myoglobin, haemoglobin, neuroglobin and cytoglobin in solid tumours and cancer cells, Acta Physiol., 202, 563-581, doi: 10.1111/j.1748-1716.2010.02205.x.

79. Li, X., Wu, Z., Wang, Y., Mei, Q., Fu, X., and Han, W. (2013) Characterization of adult alpha- and beta-globin elevated by hydrogen peroxide in cervical cancer cells that play a cytoprotective role against oxidative insults, PLoS One, 8, e54342, doi: 10.1371/journal.pone.0054342.

80. Patgaonkar, M., Aranha, C., Bhonde, G., and Reddy, K. V. (2011) Identification and characterization of anti-microbial peptides from rabbit vaginal fluid, Vet. Immunol. Immunopathol., 139, 176-186, doi: 10.1016/j.vetimm.2010.10.012.

81. Saha, D., Koli, S., Patgaonkar, M., and Reddy, K. V. (2017) Expression of hemoglobin-alpha and beta subunits in human vaginal epithelial cells and their functional significance, PLoS One, 12, e0171084, doi: 10.1371/journal.pone.0171084.

82. Coates, C. J., and Decker, H. (2017) Immunological properties of oxygen-transport proteins: hemoglobin, hemocyanin and hemerythrin, Cell. Mol. Life Sci., 74, 293-317, doi: 10.1007/s00018-016-2326-7.

83. Jeney, V., Eaton, J. W., Balla, G., and Balla, J. (2013) Natural history of the bruise: formation, elimination, and biological effects of oxidized hemoglobin, Oxid. Med. Cellular Longev., 2013, 703571, doi: 10.1155/2013/703571.

84. Shaver, C. M., Upchurch, C. P., Janz, D. R., Grove, B. S., Putz, N. D., et al. (2016) Cell-free hemoglobin: a novel mediator of acute lung injury, Am. J. Physiol. Lung Cell. Mol. Physiol., 310, L532-541, doi: 10.1152/ajplung.00155.2015.

85. Zhong, Q., Zhou, K., Liang, Q. L., Lin, S., Wang, Y. C., et al. (2016) Interleukin-23 secreted by activated macrophages drives gammadeltaT cell production of interleukin-17 to aggravate secondary injury after intracerebral hemorrhage, J. Am. Heart Assoc., 5, doi: 10.1161/JAHA.116.004340.

86. Li, D., Dong, H., Li, S., Munir, M., Chen, J., et al. (2013) Hemoglobin subunit beta interacts with the capsid protein and antagonizes the growth of classical swine fever virus, J. Virol., 87, 5707-5717, doi: 10.1128/JVI.03130-12.

87. Yang, Q., Bai, S. Y., Li, L. F., Li, S., Zhang, Y., et al. (2019) Human hemoglobin subunit beta functions as a pleiotropic regulator of RIG-I/MDA5-mediated antiviral innate immune responses, J. Virol., 93, doi: 10.1128/JVI.00718-19.

88. Masoumi, Z., Erlandsson, L., Hansson, E., Magnusson, M., Mezey, E., et al. (2021) Hypoxia-induced alpha-globin expression in syncytiotrophoblasts mimics the pattern observed in preeclamptic placentas, Int. J. Mol. Sci., 22, doi: 10.3390/ijms22073357.

89. Derakhshani, A., Safarpour, H., Abdoli Shadbad, M., Hemmat, N., Leone, P., et al. (2021) The role of hemoglobin subunit delta in the immunopathy of multiple sclerosis: mitochondria matters, Front. Immunol., 12, 709173, doi: 10.3389/fimmu.2021.709173.

90. Liu, L., Zeng, M., and Stamler, J. S. (1999) Hemoglobin induction in mouse macrophages, Proc. Natl. Acad. Sci. USA, 96, 6643-6647, doi: 10.1073/pnas.96.12.6643.

91. Zheng, Y., Miyamoto, D. T., Wittner, B. S., Sullivan, J. P., Aceto, N., et al. (2017) Expression of beta-globin by cancer cells promotes cell survival during blood-borne dissemination, Nat. Commun., 8, 14344, doi: 10.1038/ncomms14344.

92. Tuteja, N., Chandra, M., Tuteja, R., and Misra, M. K. (2004) Nitric oxide as a unique bioactive signaling messenger in physiology and pathophysiology, J. Biomed. Biotechnol., 2004, 227-237, doi: 10.1155/S1110724304402034.

93. Kleschyov, A. L. (2017) The NO-heme signaling hypothesis, Free Radic. Biol. Med., 112, 544-552, doi: 10.1016/j.freeradbiomed.2017.08.025.

94. Lechauve, C., Butcher, J. T., Freiwan, A., Biwer, L. A., Keith, J. M., et al. (2018) Endothelial cell alpha-globin and its molecular chaperone alpha-hemoglobin-stabilizing protein regulate arteriolar contractility, J. Clin. Invest., 128, 5073-5082, doi: 10.1172/JCI99933.

95. Parikh, J., Kapela, A., and Tsoukias, N. M. (2017) Can endothelial hemoglobin-alpha regulate nitric oxide vasodilatory signaling? Am. J. Physiol. Heart Circ. Physiol., 312, H854-H866, doi: 10.1152/ajpheart.00315.2016.

96. Shu, X., Ruddiman, C. A., Keller, T. C. S. 4th., Keller, A. S., Yang, Y., et al. (2019) Heterocellular contact can dictate arterial function, Circ. Res., 124, 1473-1481, doi: 10.1161/CIRCRESAHA.118.313926.

97. Straub, A. C., Lohman, A. W., Billaud, M., Johnstone, S. R., Dwyer, S. T., et al. (2012) Endothelial cell expression of haemoglobin alpha regulates nitric oxide signalling, Nature, 491, 473-477, doi: 10.1038/nature11626.

98. Alvarez, R. A., Miller, M. P., Hahn, S. A., Galley, J. C., Bauer, E., et al. (2017) Targeting pulmonary endothelial hemoglobin alpha improves nitric oxide signaling and reverses pulmonary artery endothelial dysfunction, Am. J. Respir. Cell Mol. Biol., 57, 733-744, doi: 10.1165/rcmb.2016-0418OC.

99. Cao, A., and Moi, P. (2002) Regulation of the globin genes, Pediatr. Res., 51, 415-421, doi: 10.1203/00006450-200204000-00003.

100. Garrick, D., De Gobbi, M., Samara, V., Rugless, M., Holland, M., et al. (2008) The role of the polycomb complex in silencing alpha-globin gene expression in nonerythroid cells, Blood, 112, 3889-3899, doi: 10.1182/blood-2008-06-161901.

101. Iarovaia, O. V., Kovina, A. P., Petrova, N. V., Razin, S. V., Ioudinkova, E. S., et al. (2018) Genetic and epigenetic mechanisms of beta-globin gene switching, Biochemistry (Moscow), 83, 381-392, doi: 10.1134/S0006297918040090.

102. Petrova, N. V., Klimenko, N. S., Kovina, A. P., Ioudinkova, E. S., Gavrilov, A. A., et al. (2021) Mechanisms mediating suppression of globin gene transcription in Danio rerio nonerythroid cells, Biochimie, 181, 96-99, doi: 10.1016/j.biochi.2020.11.021.

103. Zhou, G. L., Xin, L., Song, W., Di, L. J., Liu, G., et al. (2006) Active chromatin hub of the mouse alpha-globin locus forms in a transcription factory of clustered housekeeping genes, Mol. Cell. Biol., 26, 5096-5105, doi: 10.1128/MCB.02454-05.

104. Feldmesser, E., Olender, T., Khen, M., Yanai, I., Ophir, R., et al. (2006) Widespread ectopic expression of olfactory receptor genes, BMC Genom., 7, 121, doi: 10.1186/1471-2164-7-121.

105. Cantor, A. B., and Orkin, S. H. (2002) Transcriptional regulation of erythropoiesis: an affair involving multiple partners, Oncogene, 21, 3368-3376, doi: 10.1038/sj.onc.1205326.

106. Higgs, D. R., Vernimmen, D., and Wood, B. (2008) Long-range regulation of alpha-globin gene expression, Adv. Genet., 61, 143-173, doi: 10.1016/S0065-2660(07)00005-3.

107. Palazon, A., Goldrath, A. W., Nizet, V., and Johnson, R. S. (2014) HIF transcription factors, inflammation, and immunity, Immunity, 41, 518-528, doi: 10.1016/j.immuni.2014.09.008.

108. Imtiyaz, H. Z., and Simon, M. C. (2010) Hypoxia-inducible factors as essential regulators of inflammation, Curr. Top. Microbiol. Immunol., 345, 105-120, doi: 10.1007/82_2010_74.

109. Hasselbalch, H. C. (2014) A role of NF-E2 in chronic inflammation and clonal evolution in essential thrombocythemia, polycythemia vera and myelofibrosis? Leuk. Res., 38, 263-266, doi: 10.1016/j.leukres.2013.07.002.

110. Jain, M. K., Sangwung, P., and Hamik, A. (2014) Regulation of an inflammatory disease: Kruppel-like factors and atherosclerosis, Arterioscler. Thromb. Vasc. Biol., 34, 499-508, doi: 10.1161/ATVBAHA.113.301925.

111. Kasai, S., Mimura, J., Ozaki, T., and Itoh, K. (2018) Emerging regulatory role of Nrf2 in iron, Heme, and hemoglobin metabolism in physiology and disease, Front. Vet. Sci., 5, 242, doi: 10.3389/fvets.2018.00242.

112. Ma, Q. (2013) Role of nrf2 in oxidative stress and toxicity, Ann. Rev. Pharmacol. Toxicol., 53, 401-426, doi: 10.1146/annurev-pharmtox-011112-140320.

113. Taniguchi, K., and Karin, M. (2018) NF-kappaB, inflammation, immunity and cancer: coming of age, Nat. Rev. Immunol., 18, 309-324, doi: 10.1038/nri.2017.142.

114. Hou, C. H., Huang, J., and Qian, R. L. (2002) Identification of a NF-kappaB site in the negative regulatory element (epsilon-NRAII) of human epsilon-globin gene and its binding protein NF-kappaB p50 in the nuclei of K562 cells, Cell Res., 12, 79-82, doi: 10.1038/sj.cr.7290113.

115. Sangwung, P., Zhou, G., Lu, Y., Liao, X., Wang, B., et al. (2017) Regulation of endothelial hemoglobin alpha expression by Kruppel-like factors, Vasc. Med., 22, 363-369, doi: 10.1177/1358863X17722211.

116. Nayak, L., Lin, Z., and Jain, M. K. (2011) “Go with the flow”: how Kruppel-like factor 2 regulates the vasoprotective effects of shear stress, Antioxid. Redox Signal., 15, 1449-1461, doi: 10.1089/ars.2010.3647.

117. McCord, J. M. (2000) The evolution of free radicals and oxidative stress, Am. J. Med., 108, 652-659, doi: 10.1016/s0002-9343(00)00412-5.

118. Heinrich, J. (1988) Cardiotocography practice. Case 16, Zentralblatt fur Gynakologie, 110, 1604-1605.

119. He, L., He, T., Farrar, S., Ji, L., Liu, T., and Ma, X. (2017) Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species, Cell. Physiol. Biochem., 44, 532-553, doi: 10.1159/000485089.

120. Petersen, A. G., Petersen, S. V., Frische, S., Drakulic, S., Golas, M. M., et al.(2018) Hemoglobin polymerization via disulfide bond formation in the hypoxia-tolerant turtle Trachemys scripta: implications for antioxidant defense and O2 transport, Am. J. Physiol. Regul. Integr. Comp. Physiol., 314, R84-R93, doi: 10.1152/ajpregu.00024.2017.