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
Souhrn
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
Zdroje
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
- Antibiotika na nachlazení nezabírají! Jak můžeme zpomalit šíření rezistence?
- FDA varuje před selfmonitoringem cukru pomocí chytrých hodinek. Jak je to v Česku?
- Prof. Jan Škrha: Metformin je bezpečný, ale je třeba jej bezpečně užívat a léčbu kontrolovat
- Ibuprofen jako alternativa antibiotik při léčbě infekcí močových cest
- Jak a kdy u celiakie začíná reakce na lepek? Možnou odpověď poodkryla čerstvá kanadská studie
Nejčtenější v tomto čísle
- DNA polymerase theta suppresses mitotic crossing over
- IKAROS is required for the measured response of NOTCH target genes upon external NOTCH signaling
- activin-2 is required for regeneration of polarity on the planarian anterior-posterior axis
- The etiology of Down syndrome: Maternal MCM9 polymorphisms increase risk of reduced recombination and nondisjunction of chromosome 21 during meiosis I within oocyte