A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression

Autoři: Zachary M. Carico aff001;  Holden C. Stefan aff002;  Megan Justice aff002;  Askar Yimit aff002;  Jill M. Dowen aff001
Působiště autorů: Cancer Epigenetics Training Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff001;  Integrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff002;  Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff003;  Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff004;  Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff005;  Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff006
Vyšlo v časopise: A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression. PLoS Genet 17(3): e1009435. doi:10.1371/journal.pgen.1009435
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009435


The cohesin complex spatially organizes interphase chromatin by bringing distal genomic loci into close physical proximity, looping out the intervening DNA. Mutation of cohesin complex subunits is observed in cancer and developmental disorders, but the mechanisms through which these mutations may contribute to disease remain poorly understood. Here, we investigate a recurrent missense mutation to the hinge domain of the cohesin subunit SMC1A, observed in acute myeloid leukemia. Engineering this mutation into murine embryonic stem cells caused widespread changes in gene expression, including dysregulation of the pluripotency gene expression program. This mutation reduced cohesin levels at promoters and enhancers, decreased DNA loops and interactions across short genomic distances, and weakened insulation at CTCF-mediated DNA loops. These findings provide insight into how altered cohesin function contributes to disease and identify a requirement for the cohesin hinge domain in three-dimensional chromatin structure.

Klíčová slova:

Cancers and neoplasms – Cloning – Gene expression – Histone modification – Chromatin – Mammalian genomics – Mutation – Yeast


1. Hnisz D, Day DS, Young RA. Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control. Cell. 2016;167: 1188–1200. doi: 10.1016/j.cell.2016.10.024 27863240

2. Dowen JMM, Fan ZPP, Hnisz D, Ren G, Abraham BJJ, Zhang LNN, et al. Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes. Cell. 2014;159: 374–387. doi: 10.1016/j.cell.2014.09.030 25303531

3. Ji X, Dadon DB, Powell BE, Fan ZP, Borges-Rivera D, Shachar S, et al. 3D Chromosome Regulatory Landscape of Human Pluripotent Cells. Cell Stem Cell. 2016;18: 262–275. doi: 10.1016/j.stem.2015.11.007 26686465

4. Smith EM, Lajoie BR, Jain G, Dekker J. Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus. Am J Hum Genet. 2016;98: 185–201. doi: 10.1016/j.ajhg.2015.12.002 26748519

5. Phillips-Cremins JE, Sauria MEG, Sanyal A, Gerasimova TI, Lajoie BR, Bell JSK, et al. Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment. Cell. 2013;153: 1281–1295. doi: 10.1016/j.cell.2013.04.053 23706625

6. Uhlmann F. SMC complexes: from DNA to chromosomes. Nat Rev Mol Cell Biol. 2016;17: 399–412. doi: 10.1038/nrm.2016.30 27075410

7. Hirano M, Hirano T. Hinge-mediated dimerization of SMC protein is essential for its dynamic interaction with DNA. EMBO J. 2002;21: 5733–5744. doi: 10.1093/emboj/cdf575 12411491

8. Haering CH, Löwe J, Hochwagen A, Nasmyth K. Molecular Architecture of SMC Proteins and the Yeast Cohesin Complex. Mol Cell. 2002;9: 773–788. doi: 10.1016/s1097-2765(02)00515-4 11983169

9. Haering CH, Schoffnegger D, Nishino T, Helmhart W, Nasmyth K, Löwe J. Structure and Stability of Cohesin’s Smc1-Kleisin Interaction. Mol Cell. 2004;15: 951–964. doi: 10.1016/j.molcel.2004.08.030 15383284

10. Gligoris TG, Scheinost JC, Bürmann F, Petela N, Chan K-L, Uluocak P, et al. Closing the cohesin ring: Structure and function of its Smc3-kleisin interface. Science. 2014;346: 963–967. doi: 10.1126/science.1256917 25414305

11. Huis in ‘t Veld PJ, Herzog F, Ladurner R, IF Davidson, Piric S, Kreidl E, et al. Characterization of a DNA exit gate in the human cohesin ring. Science (80-). 2014;346: 968–972. doi: 10.1126/science.1256904 25414306

12. Wells JN, Gligoris TG, Nasmyth KA, Marsh JA. Evolution of condensin and cohesin complexes driven by replacement of Kite by Hawk proteins. Current Biology. Cell Press; 2017. pp. R17–R18. doi: 10.1016/j.cub.2016.11.050 28073014

13. Shi Z, Shi Z, Gao H, Bai X, Yu H. Cryo-EM structure of the human cohesin-NIPBL-DNA complex. Science. 2020;368: 1454–1459. doi: 10.1126/science.abb0981 32409525

14. Li Y, Muir KW, Bowler MW, Metz J, Haering CH, Panne D. Structural basis for Scc3-dependent cohesin recruitment to chromatin. Elife. 2018;7. doi: 10.7554/eLife.38356 30109982

15. Hassler M, Shaltiel IA, Haering CH. Towards a Unified Model of SMC Complex Function. Curr Biol. 2018;28: R1266–R1281. doi: 10.1016/j.cub.2018.08.034 30399354

16. Singh VP, Gerton JL. Cohesin and human disease: lessons from mouse models. Curr Opin Cell Biol. 2015;37: 9–17. doi: 10.1016/j.ceb.2015.08.003 26343989

17. Liu J, Zhang Z, Bando M, Itoh T, Deardorff MA, Clark D, et al. Transcriptional Dysregulation in NIPBL and Cohesin Mutant Human Cells. PLOS Biol. 2009;7: e1000119. doi: 10.1371/journal.pbio.1000119 19468298

18. Fisher JB, McNulty M, Burke MJ, Crispino JD, Rao S. Cohesin Mutations in Myeloid Malignancies. Trends in Cancer. 2017;3: 282–293. doi: 10.1016/j.trecan.2017.02.006 28626802

19. Katainen R, Dave K, Pitkanen E, Palin K, Kivioja T, Valimaki N, et al. CTCF/cohesin-binding sites are frequently mutated in cancer. Nat Genet. 2015;47: 818–821. doi: 10.1038/ng.3335 26053496

20. Hill VK, Kim J-S, Waldman T. Cohesin mutations in human cancer. Biochim Biophys Acta. 2016;1866: 1–11. doi: 10.1016/j.bbcan.2016.05.002 27207471

21. Mullenders J, Aranda-Orgilles B, Lhoumaud P, Keller M, Pae J, Wang K, et al. Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms. J Exp Med. 2015;212: 1833–1850. doi: 10.1084/jem.20151323 26438359

22. Mazumdar C, Shen Y, Xavy S, Zhao F, Reinisch A, Li R, et al. Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation. Cell Stem Cell. 2015;17: 675–688. doi: 10.1016/j.stem.2015.09.017 26607380

23. Viny AD, Ott CJ, Spitzer B, Rivas M, Meydan C, Papalexi E, et al. Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis. J Exp Med. 2015;212: 1819–32. doi: 10.1084/jem.20151317 26438361

24. Galeev R, Baudet A, Kumar P, Rundberg Nilsson A, Nilsson B, Soneji S, et al. Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs. Cell Rep. 2016;14: 2988–3000. doi: 10.1016/j.celrep.2016.02.082 26997282

25. Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, et al. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res. 2017;45: D777–D783. doi: 10.1093/nar/gkw1121 27899578

26. Kim J-S, He X, Orr B, Wutz G, Hill V, Peters J-M, et al. Intact Cohesion, Anaphase, and Chromosome Segregation in Human Cells Harboring Tumor-Derived Mutations in STAG2. Sullivan BA, editor. PLOS Genet. 2016;12: e1005865. doi: 10.1371/journal.pgen.1005865 26871722

27. Bompadre O, Andrey G. Chromatin topology in development and disease. Curr Opin Genet Dev. 2019;55: 32–38. doi: 10.1016/j.gde.2019.04.007 31125724

28. Vian L, Pękowska A, Rao SSP, Kieffer-Kwon K-R, Jung S, Baranello L, et al. The Energetics and Physiological Impact of Cohesin Extrusion. Cell. 2018;173: 1165–1178.e20. doi: 10.1016/j.cell.2018.03.072 29706548

29. Davidson IF, Bauer B, Goetz D, Tang W, Wutz G, Peters J-M. DNA loop extrusion by human cohesin. Science. 2019;366: 1338–1345. doi: 10.1126/science.aaz3418 31753851

30. Kim Y, Shi Z, Zhang H, Finkelstein IJ, Yu H. Human cohesin compacts DNA by loop extrusion. Science. 2019;366: 1345–1349. doi: 10.1126/science.aaz4475 31780627

31. Srinivasan M, Scheinost JC, Petela NJ, Gligoris TG, Wissler M, Ogushi S, et al. The Cohesin Ring Uses Its Hinge to Organize DNA Using Non-topological as well as Topological Mechanisms. Cell. 2018;173: 1508–1519.e18. doi: 10.1016/j.cell.2018.04.015 29754816

32. Petela NJ, Gligoris TG, Metson J, Lee B-G, Voulgaris M, Hu B, et al. Scc2 Is a Potent Activator of Cohesin’s ATPase that Promotes Loading by Binding Scc1 without Pds5. Mol Cell. 2018;70: 1134–1148.e7. doi: 10.1016/j.molcel.2018.05.022 29932904

33. Mishra A, Hu B, Kurze A, Beckouët F, Farcas A-M, Dixon SE, et al. Both interaction surfaces within cohesin’s hinge domain are essential for its stable chromosomal association. Curr Biol. 2010;20: 279–89. doi: 10.1016/j.cub.2009.12.059 20153193

34. Kurze A, Michie KA, Dixon SE, Mishra A, Itoh T, Khalid S, et al. A positively charged channel within the Smc1/Smc3 hinge required for sister chromatid cohesion. EMBO J. 2011;30: 364–378. doi: 10.1038/emboj.2010.315 21139566

35. Chapard C, Jones R, van Oepen T, Scheinost JC, Nasmyth K, Oepen T van, et al. Sister DNA Entrapment between Juxtaposed Smc Heads and Kleisin of the Cohesin Complex. Mol Cell. 2019;75: 224–237. doi: 10.1016/j.molcel.2019.05.023 31201089

36. Nichols MH, Corces VG. A tethered-inchworm model of SMC DNA translocation. Nat Struct Mol Biol. 2018;25: 906–910. doi: 10.1038/s41594-018-0135-4 30250225

37. Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, et al. Super-Enhancers in the Control of Cell Identity and Disease. Cell. 2013;155: 934–947. doi: 10.1016/j.cell.2013.09.053 24119843

38. Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, van Berkum NL, et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature. 2010;467: 430–435. doi: 10.1038/nature09380 20720539

39. Aloia L, Di Stefano B, Di Croce L. Polycomb complexes in stem cells and embryonic development. Development (Cambridge). Oxford University Press for The Company of Biologists Limited; 2013. pp. 2525–2534. doi: 10.1242/dev.091553 23715546

40. Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes. Cell. 2013;153: 307–319. doi: 10.1016/j.cell.2013.03.035 23582322

41. Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P, et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med. 2011;17: 1086–1093. doi: 10.1038/nm.2415 21873988

42. ten Berge D, Koole W, Fuerer C, Fish M, Eroglu E, Nusse R. Wnt Signaling Mediates Self-Organization and Axis Formation in Embryoid Bodies. Cell Stem Cell. 2008;3: 508–518. doi: 10.1016/j.stem.2008.09.013 18983966

43. Später D, Hansson EM, Zangi L, Chien KR. How to make a cardiomyocyte. Dev. 2014;141: 4418–4431. doi: 10.1242/dev.091538 25406392

44. Zhao Z, Shilatifard A. Epigenetic modifications of histones in cancer. Genome Biology. BioMed Central Ltd.; 2019. pp. 1–16. doi: 10.1186/s13059-019-1870-5 31747960

45. Ross-Innes CS, Stark R, Teschendorff AE, Holmes KA, Ali HR, Dunning MJ. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature. 2012;481: 389–393. doi: 10.1038/nature10730 22217937

46. Durand NC, Shamim MS, Machol I, Rao SSP, Huntley MH, Lander ES, et al. Juicer Provides a One-Click System for Analyzing Loop-Resolution Hi-C Experiments. Cell Syst. 2016;3: 95–8. doi: 10.1016/j.cels.2016.07.002 27467249

47. Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485: 376–380. doi: 10.1038/nature11082 22495300

48. Crane E, Bian Q, McCord RP, Lajoie BR, Wheeler BS, Ralston EJ, et al. Condensin-driven remodelling of X chromosome topology during dosage compensation. Nature. 2015;523: 240–244. doi: 10.1038/nature14450 26030525

49. Rao SSP, Huntley MH, Durand NC, Stamenova EK, Bochkov ID, Robinson JT, et al. A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping. Cell. 2014;159: 1665–1680. doi: 10.1016/j.cell.2014.11.021 25497547

50. Rao SSP, Huang S-C, Glenn St Hilaire B, Engreitz JM, Perez EM, Kieffer-Kwon K-R, et al. Cohesin Loss Eliminates All Loop Domains. Cell. 2017;171: 305–320.e24. doi: 10.1016/j.cell.2017.09.026 28985562

51. Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, et al. Cohesin’s binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins. Mol Cell. 2000;5: 243–254. doi: 10.1016/s1097-2765(00)80420-7 10882066

52. Watrin E, Schleiffer A, Tanaka K, Eisenhaber F, Nasmyth K, Peters J-M. Human Scc4 Is Required for Cohesin Binding to Chromatin, Sister-Chromatid Cohesion, and Mitotic Progression. Curr Biol. 2006;16: 863–874. doi: 10.1016/j.cub.2006.03.049 16682347

53. Muñoz S, Minamino M, Casas-Delucchi CS, Patel H, Uhlmann F. A Role for Chromatin Remodeling in Cohesin Loading onto Chromosomes. Mol Cell. 2019;0. doi: 10.1016/j.molcel.2019.02.027 30922844

54. Haarhuis JHI, van der Weide RH, Blomen VA, Yáñez-Cuna JO, Amendola M, van Ruiten MS, et al. The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension. Cell. 2017;169: 693–707.e14. doi: 10.1016/j.cell.2017.04.013 28475897

55. Smith E, Shilatifard A. Enhancer biology and enhanceropathies. Nat Struct Mol Biol. 2014;21: 210–219. doi: 10.1038/nsmb.2784 24599251

56. Bradner JE, Hnisz D, Young RA. Transcriptional Addiction in Cancer. Cell. 2017;168: 629–643. doi: 10.1016/j.cell.2016.12.013 28187285

57. Schaaf CA, Kwak H, Koenig A, Misulovin Z, Gohara DW, Watson A, et al. Genome-Wide Control of RNA Polymerase II Activity by Cohesin. PLoS Genet. 2013;9: e1003382. doi: 10.1371/journal.pgen.1003382 23555293

58. Dowen JM, Bilodeau S, Orlando DA, Hübner MR, Abraham BJ, Spector DL, et al. Multiple Structural Maintenance of Chromosome Complexes at Transcriptional Regulatory Elements. Stem Cell Reports. 2013;1: 371–378. doi: 10.1016/j.stemcr.2013.09.002 24286025

59. Arruda NL, Carico ZM, Justice M, Liu YF, Zhou J, Stefan HC, et al. Distinct and overlapping roles of STAG1 and STAG2 in cohesin localization and gene expression in embryonic stem cells. Epigenetics Chromatin. 2020;13: 32. doi: 10.1186/s13072-020-00353-9 32778134

60. Zuin J, Dixon JR, van der Reijden MIJA, Ye Z, Kolovos P, Brouwer RWW, et al. Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc Natl Acad Sci. 2014;111: 996–1001. doi: 10.1073/pnas.1317788111 24335803

61. Bonev B, Cavalli G. Organization and function of the 3D genome. Nat Rev Genet. 2016;17: 661–678. doi: 10.1038/nrg.2016.112 27739532

62. Heidinger-Pauli JM, Mert O, Davenport C, Guacci V, Koshland D. Systematic Reduction of Cohesin Differentially Affects Chromosome Segregation, Condensation, and DNA Repair. Curr Biol. 2010;20: 957–963. doi: 10.1016/j.cub.2010.04.018 20451387

63. McIntyre J, Muller EGD, Weitzer S, Snydsman BE, Davis TN, Uhlmann F. In vivo analysis of cohesin architecture using FRET in the budding yeast Saccharomyces cerevisiae. EMBO J. 2007;26: 3783–93. doi: 10.1038/sj.emboj.7601793 17660750

64. Xu X, Kanai R, Nakazawa N, Wang L, Toyoshima C, Yanagida M. Suppressor mutation analysis combined with 3D modeling explains cohesin’s capacity to hold and release DNA. Proc Natl Acad Sci U S A. 2018;115: E4833–E4842. doi: 10.1073/pnas.1803564115 29735656

65. Viny AD, Bowman RL, Liu Y, Lavallée V-P, Eisman SE, Xiao W, et al. Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation. Cell Stem Cell. 2019;25: 682–696.e8. doi: 10.1016/j.stem.2019.08.003 31495782

66. Vicente-Dueñas C, Hauer J, Cobaleda C, Borkhardt A, Sánchez-García I. Epigenetic Priming in Cancer Initiation. Trends in cancer. 2018;4: 408–417. doi: 10.1016/j.trecan.2018.04.007 29860985

67. Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: From clonal haematopoiesis to secondary leukaemia. Nature Reviews Cancer. Nature Publishing Group; 2017. pp. 5–19. doi: 10.1038/nrc.2016.112 27834397

68. Justice M, Carico ZM, Stefan HC, Dowen JM. A WIZ/Cohesin/CTCF Complex Anchors DNA Loops to Define Gene Expression and Cell Identity. Cell Rep. 2020;31: 107503. doi: 10.1016/j.celrep.2020.03.067 32294452

69. Behringer R, Gertsenstein M, Nagy KV, Nagy A. Differentiating Mouse Embryonic Stem Cells into Embryoid Bodies by Hanging-Drop Cultures. Cold Spring Harb Protoc. 2016;2016: pdb.prot092429. doi: 10.1101/pdb.prot092429 27934689

70. Langmead B, Trapnell C, Pop M, Salzberg SL. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009;10. doi: 10.1186/gb-2009-10-3-r25 19261174

71. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinforma Appl NOTE. 2009;25: 2078–2079. doi: 10.1093/bioinformatics/btp352 19505943

72. Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26. doi: 10.1093/bioinformatics/btq033 20110278

73. Zhang Y, Liu T, Meyer CAA, Eeckhoute J, Johnson DSS, Bernstein BEE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9: R137. doi: 10.1186/gb-2008-9-9-r137 18798982

74. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The Human Genome Browser at UCSC. Genome Res. 2002;12: 996–1006. doi: 10.1101/gr.229102 12045153

75. Ramírez F, Ryan DP, Bj¨ B, Grüning B, Grüning G, Bhardwaj V, et al. deepTools2: a next generation web server for deep-sequencing data analysis. Web Serv issue Publ online. 2016;44. doi: 10.1093/nar/gkw257 27079975

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

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

78. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25. doi: 10.1186/1471-2105-10-25 19154573

79. Durand NC, Robinson JT, Shamim MS, Machol I, Mesirov JP, Lander ES, et al. Juicebox Provides a Visualization System for Hi-C Contact Maps with Unlimited Zoom. Cell Syst. 2016;3: 99–101. doi: 10.1016/j.cels.2015.07.012 27467250

80. Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, et al. Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome. Science (80-). 2009;326: 289–293. doi: 10.1126/science.1181369 19815776

81. 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: 576–589. doi: 10.1016/j.molcel.2010.05.004 20513432

82. Rueden CT, Schindelin J, Hiner MC, DeZonia BE, Walter AE, Arena ET, et al. ImageJ2: ImageJ for the next generation of scientific image data. BMC Bioinformatics. 2017;18: 529. doi: 10.1186/s12859-017-1934-z 29187165

Článek vyšel v časopise

PLOS Genetics

2021 Číslo 3
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
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.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Zapomenuté heslo

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


Nemáte účet?  Registrujte se