#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Ush regulates hemocyte-specific gene expression, fatty acid metabolism and cell cycle progression and cooperates with dNuRD to orchestrate hematopoiesis


Autoři: Jonathan Lenz aff001;  Robert Liefke aff001;  Julianne Funk aff003;  Samuel Shoup aff001;  Andrea Nist aff004;  Thorsten Stiewe aff004;  Robert Schulz aff005;  Yumiko Tokusumi aff005;  Lea Albert aff006;  Hartmann Raifer aff007;  Klaus Förstemann aff008;  Olalla Vázquez aff006;  Tsuyoshi Tokusumi aff005;  Nancy Fossett aff009;  Alexander Brehm aff001
Působiště autorů: Institute of Molecular Biology and Tumor Research, Biomedical Research Center, Philipps-University, Marburg, Germany aff001;  Department of Hematology, Oncology and Immunology, University Hospital Giessen and Marburg, Marburg, Germany aff002;  Institute of Molecular Oncology, Philipps-University, Marburg, Germany aff003;  Genomics Core Facility, Institute of Molecular Oncology, Member of the German Center for Lung Research (DZL), Philipps-University, Marburg, Germany aff004;  Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America aff005;  Faculty of Chemistry, Philipps-University, Marburg, Germany aff006;  Flow Cytometry Core Facility, Institute for Medical Microbiology and Hospital Hygiene, Biomedical Research Center, Philipps-University, Marburg, Germany aff007;  Gene Center and Dept. of Biochemistry, Ludwig-Maximilians-Universität, München, Germany aff008;  Center for Vascular and Inflammatory Diseases and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America aff009
Vyšlo v časopise: Ush regulates hemocyte-specific gene expression, fatty acid metabolism and cell cycle progression and cooperates with dNuRD to orchestrate hematopoiesis. PLoS Genet 17(2): e1009318. doi:10.1371/journal.pgen.1009318
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009318

Souhrn

The generation of lineage-specific gene expression programmes that alter proliferation capacity, metabolic profile and cell type-specific functions during differentiation from multipotent stem cells to specialised cell types is crucial for development. During differentiation gene expression programmes are dynamically modulated by a complex interplay between sequence-specific transcription factors, associated cofactors and epigenetic regulators. Here, we study U-shaped (Ush), a multi-zinc finger protein that maintains the multipotency of stem cell-like hemocyte progenitors during Drosophila hematopoiesis. Using genomewide approaches we reveal that Ush binds to promoters and enhancers and that it controls the expression of three gene classes that encode proteins relevant to stem cell-like functions and differentiation: cell cycle regulators, key metabolic enzymes and proteins conferring specific functions of differentiated hemocytes. We employ complementary biochemical approaches to characterise the molecular mechanisms of Ush-mediated gene regulation. We uncover distinct Ush isoforms one of which binds the Nucleosome Remodeling and Deacetylation (NuRD) complex using an evolutionary conserved peptide motif. Remarkably, the Ush/NuRD complex specifically contributes to the repression of lineage-specific genes but does not impact the expression of cell cycle regulators or metabolic genes. This reveals a mechanism that enables specific and concerted modulation of functionally related portions of a wider gene expression programme. Finally, we use genetic assays to demonstrate that Ush and NuRD regulate enhancer activity during hemocyte differentiation in vivo and that both cooperate to suppress the differentiation of lamellocytes, a highly specialised blood cell type. Our findings reveal that Ush coordinates proliferation, metabolism and cell type-specific activities by isoform-specific cooperation with an epigenetic regulator.

Klíčová slova:

Cell cycle and cell division – Cell differentiation – Drosophila melanogaster – Gene expression – Gene regulation – Hemocytes – Invertebrate genomics – Transcriptional control


Zdroje

1. Kato H, Igarashi K. To be red or white: lineage commitment and maintenance of the hematopoietic system by the "inner myeloid". Haematologica. 2019;104(10):1919–27. Epub 2019/09/14. doi: 10.3324/haematol.2019.216861 31515352.

2. DeVilbiss AW, Tanimura N, McIver SC, Katsumura KR, Johnson KD, Bresnick EH. Navigating Transcriptional Coregulator Ensembles to Establish Genetic Networks: A GATA Factor Perspective. Curr Top Dev Biol. 2016;118:205–44. Epub 2016/05/04. doi: 10.1016/bs.ctdb.2016.01.003 27137658.

3. Banerjee U, Girard JR, Goins LM, Spratford CM. Drosophila as a Genetic Model for Hematopoiesis. Genetics. 2019;211(2):367–417. doi: 10.1534/genetics.118.300223 30733377; PubMed Central PMCID: PMC6366919.

4. Cubadda Y, Heitzler P, Ray RP, Bourouis M, Ramain P, Gelbart W, et al. u-shaped encodes a zinc finger protein that regulates the proneural genes achaete and scute during the formation of bristles in Drosophila. Genes Dev. 1997;11(22):3083–95. doi: 10.1101/gad.11.22.3083 9367989; PubMed Central PMCID: PMC316693.

5. Fossett N, Schulz RA. Functional conservation of hematopoietic factors in Drosophila and vertebrates. Differentiation. 2001;69(2-3):83–90. doi: 10.1046/j.1432-0436.2001.690202.x 11798069.

6. Fossett N, Tevosian SG, Gajewski K, Zhang Q, Orkin SH, Schulz RA. The Friend of GATA proteins U-shaped, FOG-1, and FOG-2 function as negative regulators of blood, heart, and eye development in Drosophila. Proc Natl Acad Sci U S A. 2001;98(13):7342–7. doi: 10.1073/pnas.131215798 11404479; PubMed Central PMCID: PMC34670.

7. Haenlin M, Cubadda Y, Blondeau F, Heitzler P, Lutz Y, Simpson P, et al. Transcriptional activity of pannier is regulated negatively by heterodimerization of the GATA DNA-binding domain with a cofactor encoded by the u-shaped gene of Drosophila. Genes Dev. 1997;11(22):3096–108. doi: 10.1101/gad.11.22.3096 9367990; PubMed Central PMCID: PMC316702.

8. Waltzer L, Bataille L, Peyrefitte S, Haenlin M. Two isoforms of Serpent containing either one or two GATA zinc fingers have different roles in Drosophila haematopoiesis. EMBO J. 2002;21(20):5477–86. doi: 10.1093/emboj/cdf545 12374748; PubMed Central PMCID: PMC129077.

9. Dragojlovic-Munther M, Martinez-Agosto JA. Extracellular matrix-modulated Heartless signaling in Drosophila blood progenitors regulates their differentiation via a Ras/ETS/FOG pathway and target of rapamycin function. Dev Biol. 2013;384(2):313–30. Epub 2013/04/23. doi: 10.1016/j.ydbio.2013.04.004 23603494; PubMed Central PMCID: PMC4256155.

10. Fossett N. Signal transduction pathways, intrinsic regulators, and the control of cell fate choice. Biochim Biophys Acta. 2013;1830(2):2375–84. Epub 2012/06/19. doi: 10.1016/j.bbagen.2012.06.005 22705942; PubMed Central PMCID: PMC3477240.

11. Gao H, Wu X, Fossett N. Upregulation of the Drosophila Friend of GATA gene U-shaped by JAK/STAT signaling maintains lymph gland prohemocyte potency. Mol Cell Biol. 2009;29(22):6086–96. doi: 10.1128/MCB.00244-09 19737914; PubMed Central PMCID: PMC2772570.

12. Muratoglu S, Hough B, Mon ST, Fossett N. The GATA factor Serpent cross-regulates lozenge and u-shaped expression during Drosophila blood cell development. Dev Biol. 2007;311(2):636–49. Epub 2007/09/18. doi: 10.1016/j.ydbio.2007.08.015 17869239; PubMed Central PMCID: PMC2132443.

13. Sorrentino RP, Tokusumi T, Schulz RA. The Friend of GATA protein U-shaped functions as a hematopoietic tumor suppressor in Drosophila. Dev Biol. 2007;311(2):311–23. doi: 10.1016/j.ydbio.2007.08.011 17936744.

14. Tokusumi Y, Tokusumi T, Stoller-Conrad J, Schulz RA. Serpent, suppressor of hairless and U-shaped are crucial regulators of hedgehog niche expression and prohemocyte maintenance during Drosophila larval hematopoiesis. Development. 2010;137(21):3561–8. doi: 10.1242/dev.053728 20876645; PubMed Central PMCID: PMC2964091.

15. Hong W, Nakazawa M, Chen YY, Kori R, Vakoc CR, Rakowski C, et al. FOG-1 recruits the NuRD repressor complex to mediate transcriptional repression by GATA-1. EMBO J. 2005;24(13):2367–78. doi: 10.1038/sj.emboj.7600703 15920470; PubMed Central PMCID: PMC1173144.

16. Fossett N, Hyman K, Gajewski K, Orkin SH, Schulz RA. Combinatorial interactions of serpent, lozenge, and U-shaped regulate crystal cell lineage commitment during Drosophila hematopoiesis. Proc Natl Acad Sci U S A. 2003;100(20):11451–6. doi: 10.1073/pnas.1635050100 14504400; PubMed Central PMCID: PMC208778.

17. Huot G, Vernier M, Bourdeau V, Doucet L, Saint-Germain E, Gaumont-Leclerc MF, et al. CHES1/FOXN3 regulates cell proliferation by repressing PIM2 and protein biosynthesis. Mol Biol Cell. 2014;25(5):554–65. Epub 2014/01/10. doi: 10.1091/mbc.E13-02-0110 24403608; PubMed Central PMCID: PMC3937083.

18. Guruharsha KG, Obar RA, Mintseris J, Aishwarya K, Krishnan RT, Vijayraghavan K, et al. Drosophila protein interaction map (DPiM): a paradigm for metazoan protein complex interactions. Fly (Austin). 2012;6(4):246–53. Epub 2012/12/12. doi: 10.4161/fly.22108 23222005; PubMed Central PMCID: PMC3519659.

19. Kunert N, Wagner E, Murawska M, Klinker H, Kremmer E, Brehm A. dMec: a novel Mi-2 chromatin remodelling complex involved in transcriptional repression. EMBO J. 2009;28(5):533–44. doi: 10.1038/emboj.2009.3 19165147; PubMed Central PMCID: PMC2657585.

20. Cismasiu VB, Adamo K, Gecewicz J, Duque J, Lin Q, Avram D. BCL11B functionally associates with the NuRD complex in T lymphocytes to repress targeted promoter. Oncogene. 2005;24(45):6753–64. doi: 10.1038/sj.onc.1208904 16091750.

21. Kloet SL, Baymaz HI, Makowski M, Groenewold V, Jansen PW, Berendsen M, et al. Towards elucidating the stability, dynamics and architecture of the nucleosome remodeling and deacetylase complex by using quantitative interaction proteomics. FEBS J. 2015;282(9):1774–85. doi: 10.1111/febs.12972 25123934.

22. Lauberth SM, Rauchman M. A conserved 12-amino acid motif in Sall1 recruits the nucleosome remodeling and deacetylase corepressor complex. J Biol Chem. 2006;281(33):23922–31. doi: 10.1074/jbc.M513461200 16707490.

23. Roche AE, Bassett BJ, Samant SA, Hong W, Blobel GA, Svensson EC. The zinc finger and C-terminal domains of MTA proteins are required for FOG-2-mediated transcriptional repression via the NuRD complex. J Mol Cell Cardiol. 2008;44(2):352–60. doi: 10.1016/j.yjmcc.2007.10.023 18067919; PubMed Central PMCID: PMC2277079.

24. Verstappen G, van Grunsven LA, Michiels C, Van de Putte T, Souopgui J, Van Damme J, et al. Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex. Hum Mol Genet. 2008;17(8):1175–83. doi: 10.1093/hmg/ddn007 18182442.

25. Kim J, Lu C, Srinivasan S, Awe S, Brehm A, Fuller MT. Blocking promiscuous activation at cryptic promoters directs cell type-specific gene expression. Science. 2017;356(6339):717–21. doi: 10.1126/science.aal3096 28522526.

26. Kreher J, Kovac K, Bouazoune K, Macinkovic I, Ernst AL, Engelen E, et al. EcR recruits dMi-2 and increases efficiency of dMi-2-mediated remodelling to constrain transcription of hormone-regulated genes. Nat Commun. 2017;8:14806. doi: 10.1038/ncomms14806 28378812; PubMed Central PMCID: PMC5382322.

27. Murawsky CM, Brehm A, Badenhorst P, Lowe N, Becker PB, Travers AA. Tramtrack69 interacts with the dMi-2 subunit of the Drosophila NuRD chromatin remodelling complex. EMBO Rep. 2001;2(12):1089–94. doi: 10.1093/embo-reports/kve252 11743021; PubMed Central PMCID: PMC1084170.

28. Baldeosingh R, Gao H, Wu X, Fossett N. Hedgehog signaling from the Posterior Signaling Center maintains U-shaped expression and a prohemocyte population in Drosophila. Dev Biol. 2018;441(1):132–45. doi: 10.1016/j.ydbio.2018.06.020 29966604; PubMed Central PMCID: PMC6064674.

29. Mandal L, Martinez-Agosto JA, Evans CJ, Hartenstein V, Banerjee U. A Hedgehog- and Antennapedia-dependent niche maintains Drosophila haematopoietic precursors. Nature. 2007;446(7133):320–4. Epub 2007/03/16. doi: 10.1038/nature05585 17361183; PubMed Central PMCID: PMC2807630.

30. Gao C, Dimitrov T, Yong KJ, Tatetsu H, Jeong HW, Luo HR, et al. Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex. Blood. 2013;121(8):1413–21. doi: 10.1182/blood-2012-04-424275 23287862; PubMed Central PMCID: PMC3578956.

31. Gao H, Baldeosingh R, Wu X, Fossett N. The Friend of GATA Transcriptional Co-Regulator, U-Shaped, Is a Downstream Antagonist of Dorsal-Driven Prohemocyte Differentiation in Drosophila. PLoS One. 2016;11(5):e0155372. Epub 2016/05/11. doi: 10.1371/journal.pone.0155372 27163255; PubMed Central PMCID: PMC4862636.

32. Tokusumi T, Sorrentino RP, Russell M, Ferrarese R, Govind S, Schulz RA. Characterization of a lamellocyte transcriptional enhancer located within the misshapen gene of Drosophila melanogaster. PLoS One. 2009;4(7):e6429. Epub 2009/07/31. doi: 10.1371/journal.pone.0006429 19641625; PubMed Central PMCID: PMC2713827.

33. Mehla K, Singh PK. Metabolic Regulation of Macrophage Polarization in Cancer. Trends Cancer. 2019;5(12):822–34. Epub 2019/12/10. doi: 10.1016/j.trecan.2019.10.007 31813459.

34. Kadri Z, Lefevre C, Goupille O, Penglong T, Granger-Locatelli M, Fucharoen S, et al. Erythropoietin and IGF-1 signaling synchronize cell proliferation and maturation during erythropoiesis. Genes Dev. 2015;29(24):2603–16. Epub 2015/12/19. doi: 10.1101/gad.267633.115 26680303; PubMed Central PMCID: PMC4699388.

35. Kadri Z, Shimizu R, Ohneda O, Maouche-Chretien L, Gisselbrecht S, Yamamoto M, et al. Direct binding of pRb/E2F-2 to GATA-1 regulates maturation and terminal cell division during erythropoiesis. PLoS Biol. 2009;7(6):e1000123. Epub 2009/06/11. doi: 10.1371/journal.pbio.1000123 19513100; PubMed Central PMCID: PMC2684697.

36. Lejon S, Thong SY, Murthy A, AlQarni S, Murzina NV, Blobel GA, et al. Insights into association of the NuRD complex with FOG-1 from the crystal structure of an RbAp48.FOG-1 complex. J Biol Chem. 2011;286(2):1196–203. doi: 10.1074/jbc.M110.195842 21047798; PubMed Central PMCID: PMC3020727.

37. Dubuissez M, Loison I, Paget S, Vorng H, Ait-Yahia S, Rohr O, et al. Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4+ T-Cell Activation. Mol Cell Biol. 2016;36(13):1881–98. Epub 2016/05/11. doi: 10.1128/MCB.00062-16 27161321; PubMed Central PMCID: PMC4911745.

38. Reddy BA, Bajpe PK, Bassett A, Moshkin YM, Kozhevnikova E, Bezstarosti K, et al. Drosophila transcription factor Tramtrack69 binds MEP1 to recruit the chromatin remodeler NuRD. Mol Cell Biol. 2010;30(21):5234–44. doi: 10.1128/MCB.00266-10 20733004; PubMed Central PMCID: PMC2953047.

39. de la Cruz AF, Edgar BA. Flow cytometric analysis of Drosophila cells. Methods Mol Biol. 2008;420:373–89. Epub 2008/07/22. doi: 10.1007/978-1-59745-583-1_24 18641961.

40. Watson JV, Chambers SH, Smith PJ. A pragmatic approach to the analysis of DNA histograms with a definable G1 peak. Cytometry. 1987;8(1):1–8. Epub 1987/01/01. doi: 10.1002/cyto.990080101 3803091.

41. Kunert N, Brehm A. Mass production of Drosophila embryos and chromatographic purification of native protein complexes. Methods Mol Biol. 2008;420:359–71. doi: 10.1007/978-1-59745-583-1_23 18641960.

42. Brehm A, Langst G, Kehle J, Clapier CR, Imhof A, Eberharter A, et al. dMi-2 and ISWI chromatin remodelling factors have distinct nucleosome binding and mobilization properties. EMBO J. 2000;19(16):4332–41. doi: 10.1093/emboj/19.16.4332 10944116; PubMed Central PMCID: PMC302042.

43. Kon C, Cadigan KM, da Silva SL, Nusse R. Developmental roles of the Mi-2/NURD-associated protein p66 in Drosophila. Genetics. 2005;169(4):2087–100. Epub 2005/02/08. doi: 10.1534/genetics.104.034595 15695365; PubMed Central PMCID: PMC1449583.

44. Martinez-Balbas MA, Tsukiyama T, Gdula D, Wu C. Drosophila NURF-55, a WD repeat protein involved in histone metabolism. Proc Natl Acad Sci U S A. 1998;95(1):132–7. Epub 1998/02/21. doi: 10.1073/pnas.95.1.132 9419341; PubMed Central PMCID: PMC18150.

45. Murawska M, Kunert N, van Vugt J, Langst G, Kremmer E, Logie C, et al. dCHD3, a novel ATP-dependent chromatin remodeler associated with sites of active transcription. Mol Cell Biol. 2008;28(8):2745–57. doi: 10.1128/MCB.01839-07 18250149; PubMed Central PMCID: PMC2293103.

46. Papp B, Muller J. Histone trimethylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins. Genes Dev. 2006;20(15):2041–54. Epub 2006/08/03. doi: 10.1101/gad.388706 16882982; PubMed Central PMCID: PMC1536056.

47. Gambetta MC, Oktaba K, Muller J. Essential role of the glycosyltransferase sxc/Ogt in polycomb repression. Science. 2009;325(5936):93–6. Epub 2009/05/30. doi: 10.1126/science.1169727 19478141.

48. Rudolph T, Yonezawa M, Lein S, Heidrich K, Kubicek S, Schafer C, et al. Heterochromatin formation in Drosophila is initiated through active removal of H3K4 methylation by the LSD1 homolog SU(VAR)3-3. Mol Cell. 2007;26(1):103–15. doi: 10.1016/j.molcel.2007.02.025 17434130.

49. Kuipers BJ, Gruppen H. Prediction of molar extinction coefficients of proteins and peptides using UV absorption of the constituent amino acids at 214 nm to enable quantitative reverse phase high-performance liquid chromatography-mass spectrometry analysis. J Agric Food Chem. 2007;55(14):5445–51. Epub 2007/06/02. doi: 10.1021/jf070337l 17539659.

50. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9(4):357–9. Epub 2012/03/06. doi: 10.1038/nmeth.1923 22388286; PubMed Central PMCID: PMC3322381.

51. Ramirez F, Dundar F, Diehl S, Gruning BA, Manke T. deepTools: a flexible platform for exploring deep-sequencing data. Nucleic Acids Res. 2014;42(Web Server issue):W187–91. Epub 2014/05/07. doi: 10.1093/nar/gku365 24799436; PubMed Central PMCID: PMC4086134.

52. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. Genome Res. 2002;12(6):996–1006. Epub 2002/06/05. doi: 10.1101/gr.229102 12045153; PubMed Central PMCID: PMC186604.

53. Afgan E, Baker D, Batut B, van den Beek M, Bouvier D, Cech M, et al. The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update. Nucleic Acids Res. 2018;46(W1):W537–W44. Epub 2018/05/24. doi: 10.1093/nar/gky379 29790989; PubMed Central PMCID: PMC6030816.

54. Liu T, Ortiz JA, Taing L, Meyer CA, Lee B, Zhang Y, et al. Cistrome: an integrative platform for transcriptional regulation studies. Genome Biol. 2011;12(8):R83. Epub 2011/08/24. doi: 10.1186/gb-2011-12-8-r83 21859476; PubMed Central PMCID: PMC3245621.

55. Huber W, Carey VJ, Gentleman R, Anders S, Carlson M, Carvalho BS, et al. Orchestrating high-throughput genomic analysis with Bioconductor. Nat Methods. 2015;12(2):115–21. Epub 2015/01/31. doi: 10.1038/nmeth.3252 25633503; PubMed Central PMCID: PMC4509590.

56. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9(9):R137. doi: 10.1186/gb-2008-9-9-r137 18798982; PubMed Central PMCID: PMC2592715.

57. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010;38(4):576–89. Epub 2010/06/02. doi: 10.1016/j.molcel.2010.05.004 20513432; PubMed Central PMCID: PMC2898526.

58. Shin H, Liu T, Manrai AK, Liu XS. CEAS: cis-regulatory element annotation system. Bioinformatics. 2009;25(19):2605–6. Epub 2009/08/20. doi: 10.1093/bioinformatics/btp479 19689956.

59. Henriques T, Scruggs BS, Inouye MO, Muse GW, Williams LH, Burkholder AB, et al. Widespread transcriptional pausing and elongation control at enhancers. Genes Dev. 2018;32(1):26–41. Epub 2018/01/31. doi: 10.1101/gad.309351.117 29378787; PubMed Central PMCID: PMC5828392.

60. Huang C, Yang F, Zhang Z, Zhang J, Cai G, Li L, et al. Mrg15 stimulates Ash1 H3K36 methyltransferase activity and facilitates Ash1 Trithorax group protein function in Drosophila. Nat Commun. 2017;8(1):1649. Epub 2017/11/22. doi: 10.1038/s41467-017-01897-3 PubMed Central PMCID: PMC5696344. 29158494

61. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21. doi: 10.1093/bioinformatics/bts635 23104886; PubMed Central PMCID: PMC3530905.

62. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30(7):923–30. Epub 2013/11/15. doi: 10.1093/bioinformatics/btt656 24227677.

63. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. doi: 10.1186/s13059-014-0550-8 25516281; PubMed Central PMCID: PMC4302049.

64. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523. Epub 2019/04/05. doi: 10.1038/s41467-019-09234-6 30944313; PubMed Central PMCID: PMC6447622.


Článek vyšel v časopise

PLOS Genetics


2021 Číslo 2
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Důležitost adherence při depresivním onemocnění
nový kurz
Autoři: MUDr. Eliška Bartečková, Ph.D.

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Všechny kurzy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#