Two transcriptionally distinct pathways drive female development in a reptile with both genetic and temperature dependent sex determination

1. Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R. Male development of chromosomally female mice transgenic for Sry. Nature. 1991;351:117–21. doi: 10.1038/351117a0 2030730

2. Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990;346:240–4. doi: 10.1038/346240a0 1695712

3. Smith CA, Roeszler KN, Ohnesorg T, Cummins DM, Farlie PG, Doran TJ, et al. The avian Z-linked gene DMRT1 is required for male sex determination in the chicken. Nature. 2009;461:267–71. doi: 10.1038/nature08298 19710650

4. Barske LA, Capel B. Blurring the edges in vertebrate sex determination. Curr Opin Genet Dev. 2008;18:499–505 doi: 10.1016/j.gde.2008.11.004 19152784

5. Capel B. Vertebrate sex determination: evolutionary plasticity of a fundamental switch. Nat Rev Genet. 2017;18:675–89. doi: 10.1038/nrg.2017.60 28804140

6. Sarre SD, Georges A, Quinn A. The ends of a continuum: Genetic and temperature-dependent sex determination in reptiles. BioEssays. 2004;26:639–45. doi: 10.1002/bies.20050 15170861

7. Holleley CE, Sarre SD, O’Meally D, Georges A. Sex reversal in reptiles: Reproductive oddity or powerful driver of evolutionary change? Sex Dev. 2016;10:279–87. doi: 10.1159/000450972 27794577

8. Holleley CE, O’Meally D, Sarre SD, Graves JAM, Ezaz T, Matsubara K, et al. Sex reversal triggers the rapid transition from genetic to temperature-dependent sex. Nature. 2015;523:79–82. doi: 10.1038/nature14574 26135451

9. Radder RS, Quinn AE, Georges A, Sarre SD, Shine R, Quinn AE, et al. Genetic evidence for co-occurrence of chromosomal and thermal sex-determining systems in a lizard. Biol Lett. 2008;4:176–8. doi: 10.1098/rsbl.2007.0583 18089519

10. Bachtrog D, Mank JE, Peichel CL, Kirkpatrick M, Otto SP, Ashman T-L, et al. Sex Determination: Why So Many Ways of Doing It? PLOS Biol. 2014;12:e1001899. doi: 10.1371/journal.pbio.1001899 24983465

11. Herpin A, Schartl M. Plasticity of gene-regulatory networks controlling sex determination: Of masters, slaves, usual suspects, newcomers, and usurpators. EMBO Rep. 2015;16:1260–74. doi: 10.15252/embr.201540667 26358957

12. Singh SK, Das D, Rhen T. Embryonic temperature programs phenotype in reptiles. Front Physiol. 2020; doi: 10.3389/fphys.2020.00035 32082193

13. Castelli MA, Whiteley SL, Georges A, Holleley CE. Cellular calcium and redox regulation: The mediator of vertebrate environmental sex determination? Biol Rev. 2020;95:680–95. doi: 10.1111/brv.12582 32027076

14. Deveson IW, Holleley CE, Blackburn J, Marshall Graves JAM, Mattick JS, Waters PD, et al. Differential intron retention in Jumonji chromatin modifier genes is implicated in reptile temperature-dependent sex determination. Sci Adv. 2017;3:e1700731. doi: 10.1126/sciadv.1700731 28630932

15. Ge C, Ye J, Weber C, Sun W, Zhang H, Zhou Y, et al. The histone demethylase KDM6B regulates temperature-dependent sex determination in a turtle species. Science. 2018;360:645–8. doi: 10.1126/science.aap8328 29748283

16. Georges A, Holleley CE. How does temperature determine sex? Science. 2018;360:601–2. doi: 10.1126/science.aat5993 29748270

17. Weber C, Zhou Y, Lee J, Looger L, Qian G, Ge C, et al. Temperature-dependent sex determination is mediated by pSTAT3 repression of Kdm6b. Science. 2020;3:303–6. doi: 10.1126/science.aaz4165 32299951

18. Quinn AE, Georges A, Sarre SD, Guarino F, Ezaz T, Graves JAM. Temperature sex reversal implies sex gene dosage in a reptile. Science. 2007;316:411. doi: 10.1126/science.1135925 17446395

19. Whiteley SL, Weisbecker V, Georges A, Gauthier ARG, Whitehead DL, Holleley CE. Developmental asynchrony and antagonism of sex determination pathways in a lizard with temperature-induced sex reversal. Sci Rep. 2018;8:1–9. doi: 10.1038/s41598-017-17765-5 29311619

20. Whiteley SL, Holleley CE, Ruscoe WA, Castelli MA, Whitehead DL, Lei J, et al. Sex determination mode does not affect body or genital development of the central bearded dragon (Pogona vitticeps). Evodevo. 2017; doi: 10.1186/s13227-017-0087-5 29225770

21. Ross A, Munger S, Capel B. Bmp7 regulates germ cell proliferation in mouse fetal gonads. Sex Dev. 2007;1:127–37. doi: 10.1159/000100034 18391523

22. Windley SP, Wilhelm D. Signaling pathways involved in mammalian sex determination and gonad development. Sex Dev. 2016;9:297–315.

23. Tang H, Brennan J, Karl J, Hamada Y, Raetzman L, Capel B. Notch signaling maintains Leydig progenitor cells in the mouse testis. Development. 2008;135:3745–53. doi: 10.1242/dev.024786 18927153

24. Krone N, Hanley NA, Arlt W. Age-specific changes in sex steroid biosynthesis and sex development. Best Pract Res Clin Endocrinol Metab. 2007;21:393–401. doi: 10.1016/j.beem.2007.06.001 17875487

25. Russell DW, Wilson JD. Steroid 5a-Rreducatse: Two genes/two enzymes. Annu Rev Biochem. 1994;63:25–61. doi: 10.1146/annurev.bi.63.070194.000325 7979239

26. Eid W, Opitz L, Biason-Lauber A. Genome-wide identification of CBX2 targets: Insights in the human sex development network. Mol Endocrinol. 2015;29:247–57. doi: 10.1210/me.2014-1339 25569159

27. Gnessi L, Basciani S, Mariani S, Arizzi M, Spera G, Wang C, et al. Leydig cell loss and spermatogenic arrest in platelet-derived growth factor (PDGF)-A-deficient mice. J Cell Biol. 2000;149:1019–25. doi: 10.1083/jcb.149.5.1019 10831606

28. Schmahl J, Rizzolo K, Soriano P. The PDGF signaling pathway controls multiple steroid-producing lineages. Genes Dev. 2008;22:3255–67. doi: 10.1101/gad.1723908 19056881

29. Chawengsaksophak K, Svingen T, Ng ET, Epp T, Spiller CM, Clark C, et al. Loss of Wnt5a disrupts primordial germ cell migration and male sexual development in mice. Biol Reprod. 2011;86:1–12.

30. Warr N, Siggers P, Bogani D, Brixey R, Pastorelli L, Yates L, et al. Sfrp1 and Sfrp2 are required for normal male sexual development in mice. Dev Biol. 2009;326:273–84. doi: 10.1016/j.ydbio.2008.11.023 19100252

31. Kollara A, Brown TJ. Variable expression of nuclear receptor coactivator 4 (NcoA4) during mouse embryonic development. J Histochem Cytochem. 2010;58:595–609. doi: 10.1369/jhc.2010.955294 20354146

32. Padua MB, Jiang T, Morse DA, Fox SC, Hatch HM, Tevosian SG. Combined loss of the GATA4 and GATA6 transcription factors in male mice disrupts testicular development and confers adrenal-like function in the testes. Endocrinology. 2015;156:1873–86. doi: 10.1210/en.2014-1907 25668066

33. Sarraj M, Chua HK, Umbers A, Loveland K, Findlay J, Stenvers KL. Differential expression of TGFBR3 (betaglycan) in mouse ovary and testis during gonadogenesis. Growth Factors. 2007;25:334–45. doi: 10.1080/08977190701833619 18236212

34. Carré GA, Couty I, Hennequet-Antier C, Govoroun MS. Gene expression profiling reveals new potential players of gonad differentiation in the chicken embryo. PLoS One. 2011;6:1–12. doi: 10.1371/journal.pone.0023959 21931629

35. Zhao L, Arsenault M, Ng ET, Longmuss E, Chau TCY, Hartwig S, et al. SOX4 regulates gonad morphogenesis and promotes male germ cell differentiation in mice. Dev Biol. 2017;423:46–56. doi: 10.1016/j.ydbio.2017.01.013 28118982

36. Adolfi MC, Nakajima RT, N RH, Schartl M. Intersex, hermaphroditism, and gonadal plasticity in vertebrates: Evolution of the Mullerian duct and Amh/Amhr2 signaling. Annu Rev Anim Biosci. 2019;7:149–72. doi: 10.1146/annurev-animal-020518-114955 30303691

37. Sekido R, Lovell-Badge R. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature. 2008;453:930–4. doi: 10.1038/nature06944 18454134

38. Rhen T, Schroeder A. Molecular mechanisms of sex determination in reptiles. Sex Dev. 2010;4:16–28. doi: 10.1159/000282495 20145384

39. Simon AR, Rai U, Fanburg BL, Cochran BH. Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol Physiol. 1998;275:C1640–52. doi: 10.1152/ajpcell.1998.275.6.C1640 9843726

40. Good SR, Thieu VT, Mathur AN, Yu Q, Stritesky GL, Yeh N, et al. Temporal induction pattern of STAT4 target genes defines potential for Th1 lineage-specific programming. J Immunol. 2009;183:3839–47. doi: 10.4049/jimmunol.0901411 19710469

41. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004;117:1281–3. doi: 10.1242/jcs.00963 15020666

42. Eggers S, Ohnesorg T, Sinclair A. Genetic regulation of mammalian gonad development. Nat Rev Endocrinol. 2014;10:673–83. doi: 10.1038/nrendo.2014.163 25246082

43. Wang DS, Kobayashi T, Zhou LY, Paul-Prasanth B, Ijiri S, Sakai F, et al. Foxl2 up-regulates aromatase gene transcription in a female-specific manner by binding to the promoter as well as interacting with Ad4 binding protein/steroidogenic factor. Mol Endocrinol. 2007;21:712–25. doi: 10.1210/me.2006-0248 17192407

44. Park M, Shin E, Won M, Kim JH, Go H, Kim HL, et al. FOXL2 interacts with steroidogenic factor-1 (SF-1) and represses SF-1-induced CYP17 transcription in granulosa cells. Mol Endocrinol. 2010;24:1024–36. doi: 10.1210/me.2009-0375 20207836

45. Lei N, Heckert LL. Sp1 and Egr1 Regulate Transcription of the Dmrt1 Gene in Sertoli Cells. Biol Reprod. 2002;66:675–84. doi: 10.1095/biolreprod66.3.675 11870074

46. Topilko P, Schneider-Maunoury S, Levi G, Trembleau A, Gourdji D, Driancourt MA, et al. Multiple pituitary and ovarian defects in Krox-24 (NGFI-A, Egr-1)- targeted mice. Mol Endocrinol. 1998;12:107–22. doi: 10.1210/mend.12.1.0049 9440815

47. Lee SL, Sadovsky Y, Swirnoff AH, Polish JA. Luteinizing hormone deficiency and female infertility in mice lacking. Science. 1996;273:1219–21. doi: 10.1126/science.273.5279.1219 8703054

48. Cutting A, Chue J, Smith CA. Just how conserved is vertebrate sex determination? Dev Dyn. 2013;242:380–7. doi: 10.1002/dvdy.23944 23390004

49. Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995;9:2266–78. doi: 10.1101/gad.9.18.2266 7557380

50. Birk OS, Casiano DE, Wassif CA, Cogliati T, Zhao L, Zhao Y, et al. The LIM homeobox gene Lhx9 is essential for mouse gonad formation. Nature. 2000;403:909–13. doi: 10.1038/35002622 10706291

51. Oréal E, Mazaud S, Picard JY, Magre S, Carré-Eusébe D. Different patterns of anti-Müllerian hormone expression, as related to DMRT1, SF-1, WT1, GATA-4, Wnt-4, and Lhx9 expression, in the chick differentiating gonads. Dev Dyn. 2002;225:221–32. doi: 10.1002/dvdy.10153 12412004

52. Wilhelm D, Englert C. The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1. Genes Dev. 2002;16:1839–51. doi: 10.1101/gad.220102 12130543

53. Duester G. Families of retinoid dehydrogenases regulating vitamin A function: Production of visual pigment and retinoic acid. Eur J Biochem. 2000;267:4315–24. doi: 10.1046/j.1432-1327.2000.01497.x 10880953

54. Bowles J, Knight D, Smith C, Wilhelm D, Richman J, Mamiya S, et al. Retinoid signaling determines germ cell fate in mice. Science. 2006;312:596–9. doi: 10.1126/science.1125691 16574820

55. Koubova J, Menke DB, Zhou Q, Cape B, Griswold MD, Page DC. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci. 2006;103:2474–9. doi: 10.1073/pnas.0510813103 16461896

56. Roes J, Choi BK, Power D, Xu P, Segal AW. Granulocyte function in grancalcin-deficient mice. Mol Cell Biol. 2003;23:826–30. doi: 10.1128/mcb.23.3.826-830.2003 12529388

57. Maki M, Kitaura Y, Satoh H, Ohkouchi S, Shibata H. Structures, functions and molecular evolution of the penta-EF-hand Ca2+-binding proteins. Biochim Biophys Acta—Proteins Proteomics. 2002;1600(1–2):51–60. doi: 10.1016/s1570-9639(02)00444-2 12445459

58. Lloyd S. Least squares quantization in PCM. IEEE Trans Inf Theory. 1982;28:129–37.

59. Nef S, Schaad O, Stallings NR, Cederroth CR, Pitetti JL, Schaer G, et al. Gene expression during sex determination reveals a robust female genetic program at the onset of ovarian development. Dev Biol. 2005;287:361–77. doi: 10.1016/j.ydbio.2005.09.008 16214126

60. Greenlee AR, Shiao MS, Snyder E, Buaas FW, Gu T, Stearns TM, et al. Deregulated sex chromosome gene expression with male germ cell-specific loss of Dicer1. PLoS One. 2012;7:1–13. doi: 10.1371/journal.pone.0046359 23056286

61. Koenig PA, Nicholls PK, Schmidt FI, Hagiwara M, Maruyama T, Frydman GH, et al. The E2 ubiquitin-conjugating enzyme UBE2J1 is required for spermiogenesis in mice. J Biol Chem. 2014;289:34490–502. doi: 10.1074/jbc.M114.604132 25320092

62. La Fortezza M, Schenk M, Cosolo A, Kolybaba A, Grass I, Classen AK. JAK/STAT signalling mediates cell survival in response to tissue stress. Dev. 2016;143:2907–19. doi: 10.1242/dev.132340 27385008

63. Paul A, Wilson S, Belham CM, Robinson CJM, Scott PH, Gould GW, et al. Stress-activated protein kinases: Activation, regulation and function. Cell Signal. 1997;9:403–10. doi: 10.1016/s0898-6568(97)00042-9 9376221

64. Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103:239–52. doi: 10.1016/s0092-8674(00)00116-1 11057897

65. Wang X, Martindale JL, Liu Y, Holbrook NJ. The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem J. 1998;333:291–300. doi: 10.1042/bj3330291 9657968

66. Martinez P, Thanasoula M, Carlos AR, Gómez-López G, Tejera AM, Schoeftner S, et al. Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites. Nat Cell Biol. 2010;12:768–80. doi: 10.1038/ncb2081 20622869

67. Teo H, Ghosh S, Luesch H, Ghosh A, Wong ET, Malik N, et al. Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression. Nat Cell Biol. 2010;12:758–67. doi: 10.1038/ncb2080 20622870

68. Gilmore TD. Introduction to NF-κB: players, pathways, perspectives. Oncogene. 2006;25:6680. doi: 10.1038/sj.onc.1209954 17072321

69. Morgan MJ, Liu Z. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2011;21:103–15. doi: 10.1038/cr.2010.178 21187859

70. Oeckinghaus A, Hayden MS, Ghosh S. Crosstalk in NF-κB signaling pathways. Nat Immunol. 2011;12:695–708. doi: 10.1038/ni.2065 21772278

71. McGuire NL, Bentley GE. Neuropeptides in the gonads: From evolution to pharmacology. Front Pharmacol. 2010;1:1–13. doi: 10.3389/fphar.2010.00001 21607058

72. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10:397–409. doi: 10.1038/nrn2647 19469025

73. Todd E V, Liu H, Muncaster S, Gemmell NJ. Bending genders: The biology of natural sex change in fish. Sex Dev. 2016 Mar;10:223–41. doi: 10.1159/000449297 27820936

74. Liu J, Liu X, Jin C, Du X, He Y, Zhang Q. Transcriptome profiling insights the feature of sex reversal induced by high temperature in tongue sole Cynoglossus semilaevis. Front Genet. 2019;10:1–15. doi: 10.3389/fgene.2019.00001 30804975

75. Wang Q, Liu K, Feng B, Zhang Z, Wang R, Tang L, et al. Gonad transcriptome analysis of high temperature induced sex reversal in Chinese Tongue Sole, Cynoglossus semilaevis. Front Genet. 2019;10:1–11. doi: 10.3389/fgene.2019.00001 30804975

76. Hattori R, Castaneda-Cortes D, Arias Padilla L, Strobl-Mazzulla P, Fernandino J. Activation of stress response axis as a key process in environment—induced sex plasticity in fish. Cell Mol Life Sci. 2020; doi: 10.1007/s00018-020-03532-9 32367192

77. Hilton JK, Rath P, Helsell CVM, Beckstein O, Van Horn WD. Understanding thermosensitive transient receptor potential channels as versatile polymodal cellular sensors. Biochemistry. 2015;54:2401–13. doi: 10.1021/acs.biochem.5b00071 25812016

78. Benham CD, Gunthorpe MJ, Davis JB. TRPV channels as temperature sensors. Cell Calcium. 2003;33:479–87. doi: 10.1016/s0143-4160(03)00063-0 12765693

79. Czerwinski M, Natarajan A, Barske L, Looger LL, Capel B. A timecourse analysis of systemic and gonadal effects of temperature on sexual development of the red-eared slider turtle Trachemys scripta elegans. Dev Biol. 2016;420:166–77. doi: 10.1016/j.ydbio.2016.09.018 27671871

80. Yatsu R, Miyagawa S, Kohno S, Saito S, Lowers RH, Ogino Y, et al. TRPV4 associates environmental temperature and sex determination in the American alligator. Sci Rep. 2015;5:1–10. doi: 10.1038/srep18581 26677944

81. Lin JQ, Zhou Q, Yang HQ, Fang LM, Tang KY, Sun L, et al. Molecular mechanism of temperature-dependent sex determination and differentiation in Chinese alligator revealed by developmental transcriptome profiling. Sci Bull. 2018;63:209–12.

82. Yatsu R, Miyagawa S, Kohno S, Parrott BB, Yamaguchi K, Ogino Y, et al. RNA-seq analysis of the gonadal transcriptome during Alligator mississippiensis temperature-dependent sex determination and differentiation. BMC Genomics. 2016;77:1–13. doi: 10.1186/s12864-016-2396-9 26810479

83. Maynard Case R, Eisner D, Gurney A, Jones O, Muallem S, Verkhratsky A. Evolution of calcium homeostasis: From birth of the first cell to an omnipresent signalling system. Cell Calcium. 2007;42:345–50. doi: 10.1016/j.ceca.2007.05.001 17574670

84. Carafoli E. The calcium-signalling saga: Tap water and protein crystals. Nat Rev Mol Cell Biol. 2003;4:326–32. doi: 10.1038/nrm1073 12671655

85. Penna E, Espino J, De Stefani D, Rizzuto R. The MCU complex in cell death. Cell Calcium. 2018;69:73–80. doi: 10.1016/j.ceca.2017.08.008 28867646

86. Hoffman NE, Zhang X, Gill DL, Shanmughapriya S, Rajan S, Jog NR, et al. Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU. Sci Signal. 2015;8:73–80. doi: 10.1126/scisignal.2005673 25737585

87. Strehler E, Caride A, Filoteo A, Xiong Y, Penniston J, Enyedi A. Plasma membrane Ca2+-ATPases as dynamic regulators of cellular calcium handling. Ann N Y Acad Sci. 2013; doi: 10.1196 23631028

88. Stocker M. Ca2+-activated K+ channels: Molecular determinants and function of the SK family. Nat Rev Neurosci. 2004;5:758–70. doi: 10.1038/nrn1516 15378036

89. Faber ESL, Sah P. Functions of SK channels in central neurons. Clin Exp Pharmacol Physiol. 2007;34:1077–83. doi: 10.1111/j.1440-1681.2007.04725.x 17714097

90. Catterall W. Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Immunol. 2004;22:485–501. doi: 10.1146/annurev.immunol.22.012703.104707 15032586

91. Campiglio M, Flucher BE. The role of auxiliary subunits for the functional diversity of voltage-gated calcium channels. J Cell Physiol. 2015;230:2019–31. doi: 10.1002/jcp.24998 25820299

92. Kumar A, Kumari S, Majhi RK, Swain N, Yadav M, Goswami C. Regulation of TRP channels by steroids: Implications in physiology and diseases. Gen Comp Endocrinol. 2015;220:23–32. doi: 10.1016/j.ygcen.2014.10.004 25449179

93. Miehe S, Crause P, Schmidt T, Löhn M, Kleemann HW, Licher T, et al. Inhibition of diacylglycerol-sensitive TRPC channels by synthetic and natural steroids. PLoS One. 2012;7:e35393. doi: 10.1371/journal.pone.0035393 22530015

94. Ramsey IS, Delling M, Clapham DE. An introduction to TRP channels. Annu Rev Physiol. 2006;68:619–47. doi: 10.1146/annurev.physiol.68.040204.100431 16460286

95. Schaefer M, Plant TD, Obukhov AG, Hofmann T, Gudermann T, Schultz G. Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5. J Biol Chem. 2000;275:17517–26. doi: 10.1074/jbc.275.23.17517 10837492

96. Brostrom MA, Brostrom CO. Calcium dynamics and endoplasmic reticular function in the regulation of protein synthesis: Implications for cell growth and adaptability. Cell Calcium. 2003;34:345–63. doi: 10.1016/s0143-4160(03)00127-1 12909081

97. Michalak M, Corbett EF, Mesaeli N, Nakamura K, Opas M. Calreticulin: One protein, one gene, many functions. Biochem J. 1999;344:281–92. 10567207

98. Dedhar S. Novel functions for calreticulin: interaction with integrins and modulation of gene expression? Trends Biochem Sci. 1994;19:269–71. doi: 10.1016/0968-0004(94)90001-9 8048166

99. Echevarria W, Leite MF, Guerra MT, Zipfel WR, Nathanson MH. Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum. Nat Cell Biol. 2003;5:440–6. doi: 10.1038/ncb980 12717445

100. Burns K, Duggan B, Atkinson EA, Famulski KS, Nemer M, Bleackley RC, et al. Modulation of gene expression by calreticulin binding to the glucocorticoid receptor. Nature. 1994;367:476–80. doi: 10.1038/367476a0 8107808

101. Michalak M, Burns K, Andrin C, Mesaeli N, Jass GH, Busaan JL, et al. Endoplasmic reticulum form of calreticulin modulates glucocorticoid- sensitive gene expression. J Biol Chem. 1996;271:29436–45. doi: 10.1074/jbc.271.46.29436 8910610

102. Wang X, Su M, Gao F, Xie W, Zeng Y, Li D, et al. Structural basis for activity of TRIC counter-ion channels in calcium release. Proc Natl Acad Sci. 2019;116:4238–43. doi: 10.1073/pnas.1817271116 30770441

103. Santamaria-Kisiel L, Rintala-Dempsey A, Shaw G. Calcium-dependent and -independent interactions of the S100 protein family. Biochem J. 2006;396:201–14. doi: 10.1042/BJ20060195 16683912

104. Heizmann C. S-100 proteins. In: Offermanns S, Rosenthal W, editors. Encyclopedia of Molecular Pharmacology. Berlin: Springer; 2008. p. 123–45.

105. Heizmann CW. S100 proteins: structure, functions and pathology. Front Biosci. 2002;7:d1356. 11991838

106. Rebecchi MJ, Pentyala SN. Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol Rev. 2000;80:1291–335. doi: 10.1152/physrev.2000.80.4.1291 11015615

107. Thannickal V, Fanburg B. Reactive oxygen species in cell signaling. Am J Physiol—Lung Cell Mol Physiol. 2000;279:1005–28. doi: 10.1152/ajplung.2000.279.6.L1005 11076791

108. Temple MD, Perrone GG, Dawes IW. Complex cellular responses to reactive oxygen species. Trends Cell Biol. 2005;15:319–26. doi: 10.1016/j.tcb.2005.04.003 15953550

109. Schenk H, Klein M, Erdbrügger W, Dröge W, Schulze-Osthoff K. Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-kappa B and AP-1. Proc Natl Acad Sci. 1994;91:1672–6. doi: 10.1073/pnas.91.5.1672 8127864

110. Matsuzawa A. Thioredoxin and redox signaling: Roles of the thioredoxin system in control of cell fate. Arch Biochem Biophys. 2017;617:101–5. doi: 10.1016/j.abb.2016.09.011 27665998

111. Van Der Vos KE, Coffer PJ. FOXO-binding partners: It takes two to tango. Oncogene. 2008;27:2289–99. doi: 10.1038/onc.2008.22 18391971

112. Tao GZ, Lehwald N, Jang KY, Baek J, Xu B, Omary MB, et al. Wnt/β-catenin signaling protects mouse liver against oxidative stress-induced apoptosis through the inhibition of forkhead transcription factor FoxO3. J Biol Chem. 2013;288:17214–24. doi: 10.1074/jbc.M112.445965 23620592

113. Xiong Y, Uys JD, Tew KD, Townsend DM. S-Glutathionylation: From molecular mechanisms to health outcomes. Antioxid Redox Signal. 2011;15:233–70. doi: 10.1089/ars.2010.3540 21235352

114. Yankovskaya V, Horsefield R, Törnroth S, Luna-Chavez C, Miyoshi H, Léger C, et al. Architecture of succinate dehydrogenase and reactive oxygen species generation. Science. 2003;299:700–4. doi: 10.1126/science.1079605 12560550

115. Mikhed Y, Görlach A, Knaus UG, Daiber A. Redox regulation of genome stability by effects on gene expression, epigenetic pathways and DNA damage/repair. Redox Biol. 2015;5:275–89. doi: 10.1016/j.redox.2015.05.008 26079210

116. Cho SS, Kim KM, Yang JH, Kim JY, Park SJ, Kim SJ, et al. Induction of REDD1 via AP-1 prevents oxidative stress-mediated injury in hepatocytes. Free Radic Biol Med [Internet]. 2018;124:221–31. Available from: doi: 10.1016/j.freeradbiomed.2018.06.014 29909290

117. Tonelli C, Chio I, Tuveson D. Transcriptional Regulation by Nrf2. Antioxidants Redox Signal. 2018;29:1727–45. doi: 10.1089/ars.2017.7342 28899199

118. Corona-Herrera GA, Arranz SE, Martínez-Palacios CA, Navarrete-Ramírez P, Toledo-Cuevas EM, Valdez-Alarcón JJ, et al. Experimental evidence of masculinization by continuous illumination in a temperature sex determination teleost (Atherinopsidae) model: is oxidative stress involved? J Fish Biol. 2018;93:229–37. doi: 10.1111/jfb.13651 29931822

119. Zhong P, Huang H. Recent progress in the research of cold-inducible RNA-binding protein. Future Sci OA. 2017;3:FSO246. doi: 10.4155/fsoa-2017-0077 29134130

120. Schroeder AL, Metzger KJ, Miller A, Rhen T. A novel candidate gene for temperature-dependent sex determination in the Common Snapping Turtle. Genetics. 2016;203:557–71. doi: 10.1534/genetics.115.182840 26936926

121. Haltenhof T, Kotte A, de Bortoli F, Schiefer S, Meinke S, Emmerichs A-K, et al. A conserved kinase-based body temperature sensor globally controls alternative splicing and gene expression. Mol Cell. 2020;78:1–13. doi: 10.1016/j.molcel.2020.03.020 32243827

122. Wang YT, Lim Y, McCall MN, Huang K-T, Haynes CM, Nehrke K, et al. Cardioprotection by the mitochondrial unfolded protein response requires ATF5. Am J Physiol Circ Physiol. 2019;317:H472–8. doi: 10.1152/ajpheart.00244.2019 31274354

123. Zhou D, Palam LR, Jiang L, Narasimhan J, Staschke KA, Wek RC. Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. J Biol Chem. 2008;283:7064–73. doi: 10.1074/jbc.M708530200 18195013

124. Furukawa F, Hamasaki S, Hara S, Uchimura T, Shiraishi E, Osafune N, et al. Heat shock factor 1 protects germ cell proliferation during early ovarian differentiation in medaka. Sci Rep. 2019;6927:1–10. doi: 10.1038/s41598-019-43472-4 31061435

125. Metchat A, Akerfelt M, Bierkamp C, Delsinne V, Sistonen L, Alexandre H, et al. Mammalian heat shock factor 1 is essential for oocyte meiosis and directly regulates Hsp90α expression. J Biol Chem. 2009;284:9521–8. doi: 10.1074/jbc.M808819200 19158073

126. Radhakrishnan S, Literman R, Neuwald J, Severin A, Valenzuela N. Transcriptomic responses to environmental temperature by turtles with temperature-dependent and genotypic sex determination assessed by RNAseq inform the genetic architecture of embryonic gonadal development. PLoS One. 2017;12:e0172044. doi: 10.1371/journal.pone.0172044 28296881

127. Kohno S, Katsu Y, Urushitani H, Ohta Y, Iguchi T, Guillette JLJ. Potential contributions of heat shock proteins to temperature-dependent sex determination in the American Alligator. Sex Dev. 2010;4:73–87. doi: 10.1159/000260374 19940440

128. Aloia L, Di Stefano B, Di Croce L. Polycomb complexes in stem cells and embryonic development. Development. 2013;140:2525–34. doi: 10.1242/dev.091553 23715546

129. Marasca F, Bodega B, Orlando V. How polycomb-mediated cell memory deals with a changing environment: Variations in PcG complexes and proteins assortment convey plasticity to epigenetic regulation as a response to environment. Bioessays. 2018;40:1–13.

130. Endoh M, Endo TA, Shinga J, Hayashi K, Farcas A, Ma KW, et al. PCGF6-PRC1 suppresses premature differentiation of mouse embryonic stem cells by regulating germ cell-related genes. Elife. 2017;6:1–26.

131. Cohen I, Bar C, Ezhkova E. Activity of PRC1 and histone H2AK119 monoubiquitination: Revising popular misconceptions. Bioessays. 2020;1900192:1–8. doi: 10.1002/bies.201900192 32196702

132. Yang CS, Chang KY, Dang J, Rana TM. Polycomb group protein Pcgf6 acts as a master regulator to maintain embryonic stem cell identity. Sci Rep. 2016;6:1–12. doi: 10.1038/s41598-016-0001-8 28442746

133. Yan Y, Zhao W, Huang Y, Tong H, Xia Y, Jiang Q, et al. Loss of polycomb group protein Pcgf1 severely compromises proper differentiation of embryonic stem cells. Sci Rep. 2017;7:1–11. doi: 10.1038/s41598-016-0028-x 28127051

134. Fursova NA, Blackledge NP, Nakayama M, Ito S, Koseki Y, Farcas AM, et al. Synergy between variant PRC1 complexes defines polycomb-mediated gene repression. Mol Cell. 2019;74:1020–36 doi: 10.1016/j.molcel.2019.03.024 31029541

135. Blackledge NP, Farcas AM, Kondo T, King HW, McGouran JF, Hanssen LLP, et al. Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell. 2014;157:1445–59. doi: 10.1016/j.cell.2014.05.004 24856970

136. Díaz N, Piferrer F. Lasting effects of early exposure to temperature on the gonadal transcriptome at the time of sex differentiation in the European sea bass, a fish with mixed genetic and environmental sex determination. BMC Genomics. 2015 Dec;16:2–16. doi: 10.1186/1471-2164-16-2 25555398

137. Yokobayashi S, Liang CY, Kohler H, Nestorov P, Liu Z, Vidal M, et al. PRC1 coordinates timing of sexual differentiation of female primordial germ cells. Nature. 2013;495:236–40. doi: 10.1038/nature11918 23486062

138. Shen H, Xu W, Lan F. Histone lysine demethylases in mammalian embryonic development. Exp Mol Med. 2017;49:e325–7. doi: 10.1038/emm.2017.57 28450736

139. Stauffer DR, Howard TL, Nyun T, Hollenberg SM. CHMP1 is a novel nuclear matrix protein affecting chromatin structure and cell-cycle progression. J Cell Sci. 2001;114:2383–93. 11559747

140. Todd E V, Ortega-Recalde O, Liu H, Lamm MS, Rutherford KM, Cross H, et al. Stress, novel sex genes and epigenetic reprogramming orchestrate socially-controlled sex change. Sci Adv. 2019;5:eaaw7006. doi: 10.1126/sciadv.aaw7006 31309157

141. Ribas L, Crespo B, Xavier D, Kuhl H, Rodríguez JM, Díaz N, et al. Characterization of the European Sea Bass (Dicentrarchus labrax) gonadal transcriptome during sexual development. Mar Biotechnol. 2019;21:359–73. doi: 10.1007/s10126-019-09886-x 30919121

142. Georges A, Li Q, Lian J, O’Meally D, Deakin J, Wang Z, et al. High-coverage sequencing and annotated assembly of the genome of the Australian dragon lizard Pogona vitticeps. Gigascience. 2015;45:1–10. doi: 10.1186/s13742-015-0085-2 26421146

143. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: Ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21. doi: 10.1093/bioinformatics/bts635 23104886

144. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–9. doi: 10.1093/bioinformatics/btp352 19505943

145. Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011;12:21–40. doi: 10.1186/1471-2105-12-21 21235786

146. Robinson MD, McCarthy DJ, Smyth GK. edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2009;26:139–40. doi: 10.1093/bioinformatics/btp616 19910308

147. RStudio: Integrated development for R. Boston: RStudio Inc; 2015.

148. McCarthy DJ, Chen Y, Smyth GK. Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 2012;40:4288–97. doi: 10.1093/nar/gks042 22287627

149. Anders S, Huber W. Differential expression analysis for sequence count data. Genome Biol. 2010;11:R106. doi: 10.1186/gb-2010-11-10-r106 20979621

150. Cox DR, Reid N. Parameter orthogonality and approximate conditional inference. J R Stat Soc B. 1987;49:1–39.

151. Chen Y, Lun ATL, Smyth GK. From reads to genes to pathways: Differential expression analysis of RNA-Seq experiments using Rsubread and the edgeR quasi-likelihood pipeline. F1000Research. 2016;5:1–49. doi: 10.12688/f1000research.8987.2 27508061

152. Lun A, Chen Y, Smyth G. It’s DE-licious: A recipe for differential expression analyses of RNA-seq experiments using quasi-likelihood methods in edgeR. In: Mathe E, Davis S, editors. Statistical Genomics. New York: Humana Press; 2016. p. 391–416.

153. Lund SP, Nettleton D, McCarthy DJ, Smyth GK. Detecting differential expression in RNA-sequence data using quasi-likelihood with shrunken dispersion estimates. Stat Appl Genet Mol Biol. 2012;11:1–42. doi: 10.1515/1544-6115.1826 23104842

154. Lun ATL, Smyth GK. No counts, no variance: allowing for loss of degrees of freedom when assessing biological variability from RNA-seq data. Stat Appl Genet Mol Biol. 2017;16:83–93. doi: 10.1515/sagmb-2017-0010 28599403

155. Phipson B, Lee S, Majewski IJ, Alexander WS, Smyth GK. Robust hyperparameter estimation protects against hypervariable genes and improves power to detect differential expression. Ann Appl Stat. 2016;10:946–63. doi: 10.1214/16-AOAS920 28367255

156. Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics. 2009;10:48. doi: 10.1186/1471-2105-10-48 19192299

157. Eden E, Lipson D, Yogev S, Yakhini Z. Discovering motifs in ranked lists of DNA sequences. PLoS Comput Biol. 2007;3:0508–22. doi: 10.1371/journal.pcbi.0030039 17381235