Uncovering Hidden Layers of Cell Cycle Regulation through Integrative Multi-omic Analysis

English version České info

How the genetic program of a cell unfolds to execute complex functions depends on a dynamic interplay between multiple steps that include transcription of DNA into mRNA, translation of mRNA into protein and post-translational degradation of mature proteins. Profiling of gene expression is traditionally based on measurements of steady-state mRNA levels, but recent studies have shown that mRNA and protein levels are highly discordant, suggesting that post-transcriptional mechanisms play a dominant role in modulating protein abundance. Here we combine measurements of mRNA, translation and protein across the mammalian cell cycle to uncover the hidden complexity of cell cycle regulation. Using this approach, we gain insights into the dynamics of protein synthesis and degradation and identify new genes and functions that cycle through cell division by periodic changes in translation or degradation rates. Integrative multi-omic analyses combining information on the transcriptome, translatome and proteome hold great promise for providing transformative biological insights in a variety of model systems.

Vyšlo v časopise: Uncovering Hidden Layers of Cell Cycle Regulation through Integrative Multi-omic Analysis. PLoS Genet 11(10): e32767. doi:10.1371/journal.pgen.1005554
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005554

Souhrn

Zdroje

1. Payne SH (2015) The utility of protein and mRNA correlation. Trends Biochem Sci 40: 1–3. doi: 10.1016/j.tibs.2014.10.010 25467744

2. Aviner R, Geiger T, Elroy-Stein O (2013) Novel proteomic approach (PUNCH-P) reveals cell cycle-specific fluctuations in mRNA translation. Genes Dev 27: 1834–1844. doi: 10.1101/gad.219105.113 23934657

3. Schwanhausser B, Gossen M, Dittmar G, Selbach M (2009) Global analysis of cellular protein translation by pulsed SILAC. Proteomics 9: 205–209. doi: 10.1002/pmic.200800275 19053139

4. Howden AJ, Geoghegan V, Katsch K, Efstathiou G, Bhushan B, et al. (2013) QuaNCAT: quantitating proteome dynamics in primary cells. Nat Methods 10: 343–346. doi: 10.1038/nmeth.2401 23474466

5. Elliott TS, Townsley FM, Bianco A, Ernst RJ, Sachdeva A, et al. (2014) Proteome labeling and protein identification in specific tissues and at specific developmental stages in an animal. Nat Biotechnol 32: 465–472. doi: 10.1038/nbt.2860 24727715

6. Heiman M, Schaefer A, Gong S, Peterson JD, Day M, et al. (2008) A translational profiling approach for the molecular characterization of CNS cell types. Cell 135: 738–748. doi: 10.1016/j.cell.2008.10.028 19013281

7. Ingolia NT, Ghaemmaghami S, Newman JR, Weissman JS (2009) Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324: 218–223. doi: 10.1126/science.1168978 19213877

8. Jovanovic M, Rooney MS, Mertins P, Przybylski D, Chevrier N, et al. (2015) Immunogenetics. Dynamic profiling of the protein life cycle in response to pathogens. Science 347: 1259038. doi: 10.1126/science.1259038 25745177

9. Schwanhausser B, Busse D, Li N, Dittmar G, Schuchhardt J, et al. (2011) Global quantification of mammalian gene expression control. Nature 473: 337–342. doi: 10.1038/nature10098 21593866

10. Kristensen AR, Gsponer J, Foster LJ (2013) Protein synthesis rate is the predominant regulator of protein expression during differentiation. Mol Syst Biol 9: 689. doi: 10.1038/msb.2013.47 24045637

11. Battle A, Khan Z, Wang SH, Mitrano A, Ford MJ, et al. (2015) Genomic variation. Impact of regulatory variation from RNA to protein. Science 347: 664–667. doi: 10.1126/science.1260793 25657249

12. Eichelbaum K, Krijgsveld J (2014) Rapid temporal dynamics of transcription, protein synthesis, and secretion during macrophage activation. Mol Cell Proteomics 13: 792–810. doi: 10.1074/mcp.M113.030916 24396086

13. Lee MV, Topper SE, Hubler SL, Hose J, Wenger CD, et al. (2011) A dynamic model of proteome changes reveals new roles for transcript alteration in yeast. Mol Syst Biol 7: 514. doi: 10.1038/msb.2011.48 21772262

14. Lu P, Vogel C, Wang R, Yao X, Marcotte EM (2007) Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation. Nat Biotechnol 25: 117–124. 17187058

15. McManus J, Cheng Z, Vogel C (2015) Next-generation analysis of gene expression regulation—comparing the roles of synthesis and degradation. Mol Biosyst.

16. Whitfield ML, Sherlock G, Saldanha AJ, Murray JI, Ball CA, et al. (2002) Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol Biol Cell 13: 1977–2000. 12058064

17. Qin X, Sarnow P (2004) Preferential translation of internal ribosome entry site-containing mRNAs during the mitotic cycle in mammalian cells. J Biol Chem 279: 13721–13728. 14739278

18. Stumpf CR, Moreno MV, Olshen AB, Taylor BS, Ruggero D (2013) The translational landscape of the mammalian cell cycle. Mol Cell 52: 574–582. doi: 10.1016/j.molcel.2013.09.018 24120665

19. Merbl Y, Refour P, Patel H, Springer M, Kirschner MW (2013) Profiling of ubiquitin-like modifications reveals features of mitotic control. Cell 152: 1160–1172. doi: 10.1016/j.cell.2013.02.007 23452859

20. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, et al. (2010) Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal 3: ra3. doi: 10.1126/scisignal.2000475 20068231

21. Ly T, Ahmad Y, Shlien A, Soroka D, Mills A, et al. (2014) A proteomic chronology of gene expression through the cell cycle in human myeloid leukemia cells. Elife 3: e01630. doi: 10.7554/eLife.01630 24596151

22. Peters JM (2006) The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 7: 644–656. 16896351

23. Sadasivam S, Duan S, DeCaprio JA (2012) The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression. Genes Dev 26: 474–489. doi: 10.1101/gad.181933.111 22391450

24. Sivan G, Aviner R, Elroy-Stein O (2011) Mitotic modulation of translation elongation factor 1 leads to hindered tRNA delivery to ribosomes. J Biol Chem 286: 27927–27935. doi: 10.1074/jbc.M111.255810 21665947

25. Pyronnet S, Dostie J, Sonenberg N (2001) Suppression of cap-dependent translation in mitosis. Genes Dev 15: 2083–2093. 11511540

26. Sivan G, Kedersha N, Elroy-Stein O (2007) Ribosomal slowdown mediates translational arrest during cellular division. Mol Cell Biol 27: 6639–6646. 17664278

27. Cambridge SB, Gnad F, Nguyen C, Bermejo JL, Kruger M, et al. (2011) Systems-wide proteomic analysis in mammalian cells reveals conserved, functional protein turnover. J Proteome Res 10: 5275–5284. doi: 10.1021/pr101183k 22050367

28. Cox J, Mann M (2012) 1D and 2D annotation enrichment: a statistical method integrating quantitative proteomics with complementary high-throughput data. BMC Bioinformatics 13 Suppl 16: S12. doi: 10.1186/1471-2105-13-S16-S12 23176165

29. Slupphaug G, Olsen LC, Helland D, Aasland R, Krokan HE (1991) Cell cycle regulation and in vitro hybrid arrest analysis of the major human uracil-DNA glycosylase. Nucleic Acids Res 19: 5131–5137. 1923798

30. Mathews MB, Bernstein RM, Franza BR Jr., Garrels JI (1984) Identity of the proliferating cell nuclear antigen and cyclin. Nature 309: 374–376. 6145097

31. Yam CH, Fung TK, Poon RY (2002) Cyclin A in cell cycle control and cancer. Cell Mol Life Sci 59: 1317–1326. 12363035

32. Pines J, Hunter T (1989) Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2. Cell 58: 833–846. 2570636

33. Tanaka M, Ueda A, Kanamori H, Ideguchi H, Yang J, et al. (2002) Cell-cycle-dependent regulation of human aurora A transcription is mediated by periodic repression of E4TF1. J Biol Chem 277: 10719–10726. 11790771

34. Fournier ML, Paulson A, Pavelka N, Mosley AL, Gaudenz K, et al. (2010) Delayed correlation of mRNA and protein expression in rapamycin-treated cells and a role for Ggc1 in cellular sensitivity to rapamycin. Mol Cell Proteomics 9: 271–284. doi: 10.1074/mcp.M900415-MCP200 19955083

35. Fischer JA, Muller-Weeks S, Caradonna S (2004) Proteolytic degradation of the nuclear isoform of uracil-DNA glycosylase occurs during the S phase of the cell cycle. DNA Repair (Amst) 3: 505–513.

36. Zhao S, Fung-Leung WP, Bittner A, Ngo K, Liu X (2014) Comparison of RNA-Seq and microarray in transcriptome profiling of activated T cells. PLoS One 9: e78644. doi: 10.1371/journal.pone.0078644 24454679

37. de Sousa Abreu R, Penalva LO, Marcotte EM, Vogel C (2009) Global signatures of protein and mRNA expression levels. Mol Biosyst 5: 1512–1526. doi: 10.1039/b908315d 20023718

38. Nagaraj N, Wisniewski JR, Geiger T, Cox J, Kircher M, et al. (2011) Deep proteome and transcriptome mapping of a human cancer cell line. Mol Syst Biol 7: 548. doi: 10.1038/msb.2011.81 22068331

39. Silva JC, Gorenstein MV, Li GZ, Vissers JP, Geromanos SJ (2006) Absolute quantification of proteins by LCMSE: a virtue of parallel MS acquisition. Mol Cell Proteomics 5: 144–156. 16219938

40. Csardi G, Franks A, Choi DS, Airoldi EM, Drummond DA (2015) Accounting for experimental noise reveals that mRNA levels, amplified by post-transcriptional processes, largely determine steady-state protein levels in yeast. PLoS Genet 11: e1005206. doi: 10.1371/journal.pgen.1005206 25950722

41. Rattray AM, Muller B (2012) The control of histone gene expression. Biochem Soc Trans 40: 880–885. doi: 10.1042/BST20120065 22817752

42. Whitfield ML, Zheng LX, Baldwin A, Ohta T, Hurt MM, et al. (2000) Stem-loop binding protein, the protein that binds the 3' end of histone mRNA, is cell cycle regulated by both translational and posttranslational mechanisms. Mol Cell Biol 20: 4188–4198. 10825184

43. Kafri R, Levy J, Ginzberg MB, Oh S, Lahav G, et al. (2013) Dynamics extracted from fixed cells reveal feedback linking cell growth to cell cycle. Nature 494: 480–483. doi: 10.1038/nature11897 23446419

44. Li JJ, Bickel PJ, Biggin MD (2014) System wide analyses have underestimated protein abundances and the importance of transcription in mammals. PeerJ 2: e270. doi: 10.7717/peerj.270 24688849

45. Consortium SM-I (2014) A comprehensive assessment of RNA-seq accuracy, reproducibility and information content by the Sequencing Quality Control Consortium. Nat Biotechnol 32: 903–914. doi: 10.1038/nbt.2957 25150838

46. May E, Jenkins JR, May P (1991) Endogenous HeLa p53 proteins are easily detected in HeLa cells transfected with mouse deletion mutant p53 gene. Oncogene 6: 1363–1365. 1886712

47. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63: 1129–1136. 2175676

48. Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92: 5510–5514. 7539918

49. Zariwala M, Liu J, Xiong Y (1998) Cyclin E2, a novel human G1 cyclin and activating partner of CDK2 and CDK3, is induced by viral oncoproteins. Oncogene 17: 2787–2798. 9840943

50. Hellmuth S, Bottger F, Pan C, Mann M, Stemmann O (2014) PP2A delays APC/C-dependent degradation of separase-associated but not free securin. EMBO J 33: 1134–1147. doi: 10.1002/embj.201488098 24781523

51. Lam YW, Lamond AI, Mann M, Andersen JS (2007) Analysis of nucleolar protein dynamics reveals the nuclear degradation of ribosomal proteins. Curr Biol 17: 749–760. 17446074

52. Donati G, Montanaro L, Derenzini M (2012) Ribosome biogenesis and control of cell proliferation: p53 is not alone. Cancer Res 72: 1602–1607. doi: 10.1158/0008-5472.CAN-11-3992 22282659

53. Russo A, Esposito D, Catillo M, Pietropaolo C, Crescenzi E, et al. (2013) Human rpL3 induces G(1)/S arrest or apoptosis by modulating p21 (waf1/cip1) levels in a p53-independent manner. Cell Cycle 12: 76–87. doi: 10.4161/cc.22963 23255119

54. Frenkel-Morgenstern M, Danon T, Christian T, Igarashi T, Cohen L, et al. (2012) Genes adopt non-optimal codon usage to generate cell cycle-dependent oscillations in protein levels. Mol Syst Biol 8: 572. doi: 10.1038/msb.2012.3 22373820

55. Gingold H, Tehler D, Christoffersen NR, Nielsen MM, Asmar F, et al. (2014) A dual program for translation regulation in cellular proliferation and differentiation. Cell 158: 1281–1292. doi: 10.1016/j.cell.2014.08.011 25215487

56. Patil A, Dyavaiah M, Joseph F, Rooney JP, Chan CT, et al. (2012) Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response. Cell Cycle 11: 3656–3665. doi: 10.4161/cc.21919 22935709

57. Mercier S, Kury S, Shaboodien G, Houniet DT, Khumalo NP, et al. (2013) Mutations in FAM111B cause hereditary fibrosing poikiloderma with tendon contracture, myopathy, and pulmonary fibrosis. Am J Hum Genet 93: 1100–1107. doi: 10.1016/j.ajhg.2013.10.013 24268661

58. Alabert C, Bukowski-Wills JC, Lee SB, Kustatscher G, Nakamura K, et al. (2014) Nascent chromatin capture proteomics determines chromatin dynamics during DNA replication and identifies unknown fork components. Nat Cell Biol 16: 281–293. doi: 10.1038/ncb2918 24561620

59. Rappsilber J, Mann M, Ishihama Y (2007) Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc 2: 1896–1906. 17703201

60. Cox J, Mann M (2008) MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 26: 1367–1372. doi: 10.1038/nbt.1511 19029910

61. Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, et al. (2011) Andromeda: a peptide search engine integrated into the MaxQuant environment. J Proteome Res 10: 1794–1805. doi: 10.1021/pr101065j 21254760

62. Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, et al. (2014) Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteomics 13: 2513–2526. doi: 10.1074/mcp.M113.031591 24942700

63. Vizcaino JA, Deutsch EW, Wang R, Csordas A, Reisinger F, et al. (2014) ProteomeXchange provides globally coordinated proteomics data submission and dissemination. Nat Biotechnol 32: 223–226. doi: 10.1038/nbt.2839 24727771