Article

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

  • Nature Communications 5, Article number: 3634 (2014)
  • doi:10.1038/ncomms4634
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Abstract

Genetic deficiencies in transcription factors can lead to the loss of certain types of cells and tissue. The steroidogenic tissue-specific nuclear receptor Ad4BP/SF-1 (NR5A1) is one such gene, because mice in which this gene is disrupted fail to develop the adrenal gland and gonads. However, the specific role of Ad4BP/SF-1 in these biological events remains unclear. Here we use chromatin immunoprecipitation sequencing to show that nearly all genes in the glycolytic pathway are regulated by Ad4BP/SF-1. Suppression of Ad4BP/SF-1 by small interfering RNA reduces production of the energy carriers ATP and nicotinamide adenine dinucleotide phosphate, as well as lowers expression of genes involved in glucose metabolism. Together, these observations may explain tissue dysgenesis as a result of Ad4BP/SF-1 gene disruption in vivo. Considering the function of estrogen-related receptor α, the present study raises the possibility that certain types of nuclear receptors regulate sets of genes involved in metabolic pathways to generate energy carriers.

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References

  1. 1.

    , & Minireview: transcriptional regulation of adrenocortical development. Endocrinology 146, 1018–1024 (2005).

  2. 2.

    et al. Sex-dependent expression of a transcription factor, Ad4BP, regulating steroidogenic P-450 genes in the gonads during prenatal and postnatal rat development. Development 120, 2787–2797 (1994).

  3. 3.

    , , & Molecular aspects of steroidogenic factor 1 (SF-1). Mol. Cell. Endocrinol. 315, 27–39 (2010).

  4. 4.

    , , , & A common trans-acting factor, Ad4-binding protein, to the promoters of steroidogenic P-450s. J. Biol. Chem. 267, 17913–17919 (1992).

  5. 5.

    , , & SF-1 a key player in the development and differentiation of steroidogenic tissues. Nucl. Recept. 1, 8 (2003).

  6. 6.

    et al. Activation of CYP11A and CYP11B gene promoters by the steroidogenic cell-specific transcription factor, Ad4BP. Mol. Endocrinol. 7, 1196–1204 (1993).

  7. 7.

    , , & Steroidogenic factor-1 binding and transcriptional activity of the cholesterol side-chain cleavage promoter in rat granulosa cells. Endocrinology 134, 1499–1508 (1994).

  8. 8.

    , , & Steroidogenic factor 1-dependent promoter activity of the human steroidogenic acute regulatory protein (StAR) gene. Biochemistry 35, 9052–9059 (1996).

  9. 9.

    , & A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77, 481–490 (1994).

  10. 10.

    & Ad4BP/SF-1, a transcription factor essential for the transcription of steroidogenic cytochrome P450 genes and for the establishment of the reproductive function. FASEB J. 10, 1569–1577 (1996).

  11. 11.

    et al. Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proc. Natl Acad. Sci. USA 92, 10939–10943 (1995).

  12. 12.

    et al. Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev. Dyn. 204, 22–29 (1995).

  13. 13.

    et al. Steroidogenic factor 1 overexpression and gene amplification are more frequent in adrenocortical tumors from children than from adults. J. Clin. Endocrinol. Metab. 95, 1458–1462 (2010).

  14. 14.

    et al. Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol. Endocrinol. 21, 2968–2987 (2007).

  15. 15.

    et al. High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors. J. Clin. Endocrinol. Metab. 95, E161–E171 (2010).

  16. 16.

    , , & Transgenic expression of Ad4BP/SF-1 in fetal adrenal progenitor cells leads to ectopic adrenal formation. Mol. Endocrinol. 23, 1657–1667 (2009).

  17. 17.

    , & Adrenocortical cell lines. Mol. Cell. Endocrinol. 228, 23–38 (2004).

  18. 18.

    et al. Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response. Proc. Natl Acad. Sci. USA 97, 14488–14493 (2000).

  19. 19.

    et al. Inhibition of adrenocortical carcinoma cell proliferation by steroidogenic factor-1 inverse agonists. J. Clin. Endocrinol. Metab. 94, 2178–2183 (2009).

  20. 20.

    et al. Steroidogenic Factor 1 (NR5A1) resides in centrosomes and maintains genomic stability by controlling centrosome homeostasis. Cell Death. Differ. 18, 1836–1844 (2011).

  21. 21.

    , & Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage. Development 134, 2349–2358 (2007).

  22. 22.

    et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).

  23. 23.

    A review of isozymes in cancer. Cancer. Res. 31, 1523–1542 (1971).

  24. 24.

    & Enolase isoenzymes. II. Hybridization studies, developmental and phylogenetic aspects. Biochim. Biophys. Acta. 405, 175–187 (1975).

  25. 25.

    DREME: motif discovery in transcription factor ChIP-seq data. Bioinformatics 27, 1653–1659 (2011).

  26. 26.

    et al. MEME SUITE: tools for motif discovery and searching. Nucleic Acids. Res. 37, W202–W208 (2009).

  27. 27.

    et al. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 28, 495–501 (2010).

  28. 28.

    et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

  29. 29.

    et al. Molecular and genetic crosstalks between mTOR and ERRalpha are key determinants of rapamycin-induced nonalcoholic fatty liver. Cell Metab. 17, 586–598 (2013).

  30. 30.

    et al. The homeobox protein Prox1 is a negative modulator of ERR{alpha}/PGC-1{alpha} bioenergetic functions. Genes Dev. 24, 537–542 (2010).

  31. 31.

    , & The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol. Cell. Biol. 17, 5400–5409 (1997).

  32. 32.

    et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA 107, 21931–21936 (2010).

  33. 33.

    , , , & The organization of histone H3 modifications as revealed by a panel of specific monoclonal antibodies. Cell Struct. Funct. 33, 61–73 (2008).

  34. 34.

    et al. Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 69, 4918–4925 (2009).

  35. 35.

    & Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am. J. Physiol. 264, C761–C782 (1993).

  36. 36.

    , & Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434 (2006).

  37. 37.

    et al. Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am. J. Physiol. Cell Physiol. 292, C125–C136 (2007).

  38. 38.

    et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66–79 (2012).

  39. 39.

    , & Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

  40. 40.

    , & SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

  41. 41.

    & Early steps in steroidogenesis: intracellular cholesterol trafficking. J. Lipid Res. 52, 2111–2135 (2011).

  42. 42.

    & Studies on the source of cholesterol used for steroid biosynthesis in cultured Leydig tumor cells. J. Biol. Chem. 257, 14231–14238 (1982).

  43. 43.

    Molecular biology of steroid hormone synthesis. Endocr. Rev. 9, 295–318 (1988).

  44. 44.

    et al. Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function. Mol. Endocrinol. 18, 1610–1619 (2004).

  45. 45.

    et al. Steroidogenic factor 1 (SF1) is essential for pituitary gonadotrope function. Development 128, 147–154 (2001).

  46. 46.

    , , , & The Drosophila estrogen-related receptor directs a metabolic switch that supports developmental growth. Cell Metab. 13, 139–148 (2011).

  47. 47.

    et al. Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. Proc. Natl Acad. Sci. USA 108, 10673–10678 (2011).

  48. 48.

    Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr. Rev. 29, 677–696 (2008).

  49. 49.

    , & Otto Warburg's contributions to current concepts of cancer metabolism. Nat. Rev. Cancer 11, 325–337 (2011).

  50. 50.

    & Genetic Aspects of Metabolic Control. Annu. Rev. Microbiol. 18, 95–110 (1964).

  51. 51.

    , & LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis. Trends Cell Biol. 14, 250–260 (2004).

  52. 52.

    , , & Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Science 252, 1296–1300 (1991).

  53. 53.

    , & The orphan receptors NGFI-B and steroidogenic factor 1 establish monomer binding as a third paradigm of nuclear receptor-DNA interaction. Mol. Cell. Biol. 13, 5794–5804 (1993).

  54. 54.

    , & TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009).

  55. 55.

    et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat. Protoc. 7, 562–578 (2012).

  56. 56.

    & Adrenocorticotropic hormone-mediated signaling cascades coordinate a cyclic pattern of steroidogenic factor 1-dependent transcriptional activation. Mol. Endocrinol. 20, 147–166 (2006).

  57. 57.

    , , & Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

  58. 58.

    et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).

  59. 59.

    et al. Small ubiquitin-like modifier 1 (SUMO-1) modification of the synergy control motif of Ad4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1) regulates synergistic transcription between Ad4BP/SF-1 and Sox9. Mol. Endocrinol. 18, 2451–2462 (2004).

  60. 60.

    , , & Transcriptional Suppression by Transient Recruitment of ARIP4 to Sumoylated nuclear receptor Ad4BP/SF-1. Mol. Biol. Cell 20, 4235–4245 (2009).

  61. 61.

    et al. p32/gC1qR is indispensable for fetal development and mitochondrial translation: importance of its RNA-binding ability. Nucleic Acids Res. 40, 9717–9737 (2012).

  62. 62.

    , , , & Ca2+ signal stimulates the expression of steroidogenic acute regulatory protein and steroidogenesis in bovine adrenal fasciculata-reticularis cells. Life Sci. 78, 2923–2930 (2006).

  63. 63.

    , & Competition for electron transfer between cytochromes P450scc and P45011 beta in rat adrenal mitochondria. Mol. Cell. Endocrinol. 95, 1–11 (1993).

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Acknowledgements

This work was supported by Grants 21249018 (K.M.) and 10007695 (T.B.) from the Japan Society for the Promotion of Science (JSPS); Grant 22132002 (K.M.) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (MEXT) KAKENHI; the Tokyo Biochemical Research Foundation (K.M.); Kyushu University Interdisciplinary Program in Education and Projects in Research Development (T.B.); the Fukuoka Foundation for Sound Health (T.B.); and Grant NSC-101-2321-B-001-001 (B.-C.C.) from the National Science Council, Taiwan. We thank Dr Megumi Tsuchiya and Ms Junko Nagai for technical assistance.

Author information

Author notes

    • Chia-Yih Wang

    Present address: Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan

Affiliations

  1. Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan

    • Takashi Baba
    • , Hiroyuki Otake
    • , Kanako Miyabayashi
    • , Yurina Shishido
    • , Yuichi Shima
    •  & Ken-Ichirou Morohashi
  2. Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan

    • Tetsuya Sato
    •  & Mikita Suyama
  3. Institute of Molecular Biology, Academia Sinica, 128 Academia Road, Nankang, Taipei 115, Taiwan

    • Chia-Yih Wang
    •  & Bon-Chu Chung
  4. Nuclear Dynamics Group, Graduate School of Frontier Biosciences, Osaka University, Yamadaoka 1-3, Osaka 565-0871, Japan

    • Hiroshi Kimura
    •  & Hidesato Ogawa
  5. Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan

    • Mikako Yagi
    •  & Dongchon Kang
  6. Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Kagamiyama 1-7-1, Higashi-Hiroshima 739-8521, Japan

    • Yasuhiro Ishihara
    •  & Takeshi Yamazaki
  7. Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811, Japan

    • Shinjiro Hino
    •  & Mitsuyoshi Nakao
  8. Advanced ICT Research Institute Kobe, National Institute of Information and Communications Technology, Iwaoka 588-2, Nishi-ku, Kobe 651-2492, Japan

    • Hidesato Ogawa
  9. Department of Advanced Medical Initiatives, JST-CREST, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan

    • Yasuyuki Ohkawa

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Contributions

T.B., H.O. (Hiroyuki Otake) and K.-I.M. conceived and designed the experimental approach and performed experiments. T.B. and K.-I.M. prepared the manuscript. T.S. and M.S. contributed to the computational analyses for mRNA-seq and ChIP-seq. K.M., Y.S. (Yuichi Shima) and Y.S. (Yurina Shishido) constructed the mRNA-seq libraries and performed gene expression analyses. C.-Y.W. and B.-C.C. performed the shRNA experiment. H.K. produced anti-H3K27Ac antibodies. M.Y. and D.K. measured ATP levels. Y.I. and T.Y. measured pregnenolone levels. S.H. and M.N. measured oxygen consumption of cells. H.O. (Hidesato Ogawa) prepared purified Ad4BP/SF-1 protein. Y.O. performed deep sequencing of the ChIP-seq and mRNA-seq libraries.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ken-Ichirou Morohashi.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Figures 1-21, Supplementary Tables 1-3 and Supplementary References

Excel files

  1. 1.

    Supplementary Data 1

    List of genes down-regulated by Ad4BP/SF-1 knockdown.

  2. 2.

    Supplementary Data 2

    List of genes up-regulated by Ad4BP/SF-1 knockdown.

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