The Role of the Arabidopsis Exosome in siRNA–Independent Silencing of Heterochromatic Loci
The exosome functions throughout eukaryotic RNA metabolism and has a prominent role in gene silencing in yeast. In Arabidopsis, exosome regulates expression of a “hidden” transcriptome layer from centromeric, pericentromeric, and other heterochromatic loci that are also controlled by small (sm)RNA-based de novo DNA methylation (RdDM). However, the relationship between exosome and smRNAs in gene silencing in Arabidopsis remains unexplored. To investigate whether exosome interacts with RdDM, we profiled Arabidopsis smRNAs by deep sequencing in exosome and RdDM mutants and also analyzed RdDM-controlled loci. We found that exosome loss had a very minor effect on global smRNA populations, suggesting that, in contrast to fission yeast, in Arabidopsis the exosome does not control the spurious entry of RNAs into smRNA pathways. Exosome defects resulted in decreased histone H3K9 dimethylation at RdDM-controlled loci, without affecting smRNAs or DNA methylation. Exosome also exhibits a strong genetic interaction with RNA Pol V, but not Pol IV, and physically associates with transcripts produced from the scaffold RNAs generating region. We also show that two Arabidopsis rrp6 homologues act in gene silencing. Our data suggest that Arabidopsis exosome may act in parallel with RdDM in gene silencing, by epigenetic effects on chromatin structure, not through siRNAs or DNA methylation.
Vyšlo v časopise:
The Role of the Arabidopsis Exosome in siRNA–Independent Silencing of Heterochromatic Loci. PLoS Genet 9(3): e32767. doi:10.1371/journal.pgen.1003411
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1003411
Souhrn
The exosome functions throughout eukaryotic RNA metabolism and has a prominent role in gene silencing in yeast. In Arabidopsis, exosome regulates expression of a “hidden” transcriptome layer from centromeric, pericentromeric, and other heterochromatic loci that are also controlled by small (sm)RNA-based de novo DNA methylation (RdDM). However, the relationship between exosome and smRNAs in gene silencing in Arabidopsis remains unexplored. To investigate whether exosome interacts with RdDM, we profiled Arabidopsis smRNAs by deep sequencing in exosome and RdDM mutants and also analyzed RdDM-controlled loci. We found that exosome loss had a very minor effect on global smRNA populations, suggesting that, in contrast to fission yeast, in Arabidopsis the exosome does not control the spurious entry of RNAs into smRNA pathways. Exosome defects resulted in decreased histone H3K9 dimethylation at RdDM-controlled loci, without affecting smRNAs or DNA methylation. Exosome also exhibits a strong genetic interaction with RNA Pol V, but not Pol IV, and physically associates with transcripts produced from the scaffold RNAs generating region. We also show that two Arabidopsis rrp6 homologues act in gene silencing. Our data suggest that Arabidopsis exosome may act in parallel with RdDM in gene silencing, by epigenetic effects on chromatin structure, not through siRNAs or DNA methylation.
Zdroje
1. ChekanovaJA, GregoryBD, ReverdattoSV, ChenH, KumarR, et al. (2007) Genome-Wide High-Resolution Mapping of Exosome Substrates Reveals Hidden Features in the Arabidopsis Transcriptome. Cell 131: 1340–1353.
2. KapranovP, WillinghamAT, GingerasTR (2007) Genome-wide transcription and the implications for genomic organization. Nature Reviews Genetics 8: 413–423.
3. WilhelmBT, MargueratS, WattS, SchubertF, WoodV, et al. (2008) Dynamic repertoire of a eukaryotic transcriptome surveyed at single-nucleotide resolution. Nature 453: 1239–1243.
4. NeilH, MalabatC, d'Aubenton-CarafaY, XuZ, SteinmetzLM, et al. (2009) Widespread bidirectional promoters are the major source of cryptic transcripts in yeast. Nature 457: 1038–1042.
5. JacquierA (2009) Applications of next-generation sequencing: The complex eukaryotic transcriptome: unexpected pervasive transcription and novel small RNAs. Nature Reviews Genetics 10: 833–844.
6. GuttmanM, RinnJL (2012) Modular regulatory principles of large non-coding RNAs. Nature 482: 339–346.
7. WangKC, YangYW, LiuB, SanyalA, Corces-ZimmermanR, et al. (2011) A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472: 120–124.
8. MoazedD (2009) Small RNAs in transcriptional gene silencing and genome defence. Nature 457: 413–420.
9. MatzkeM, KannoT, DaxingerL, HuettelB, MatzkeAJ (2009) RNA-mediated chromatin-based silencing in plants. Current Opinion in Cell Biology 21: 367–376.
10. BelostotskyD (2009) Exosome complex and pervasive transcription in eukaryotic genomes. Current Opinion in Cell Biology 21: 352–358 doi:10.1016/j.ceb.2009.04.011.
11. WyersF, RougemailleM, BadisG, RousselleJ-C, DufourM-E, et al. (2005) Cryptic pol II transcripts are degraded by a nuclear quality control pathway involving a new poly(A) polymerase. Cell 121: 725–737.
12. KapranovP, ChengJ, DikeS, NixDA, DuttaguptaR, et al. (2007) RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316: 1484–1488.
13. SeilaAC, CalabreseJM, LevineSS, YeoGW, RahlPB, et al. (2008) Divergent transcription from active promoters. Science 322: 1849–1851.
14. PrekerP, NielsenJ, KammlerS, Lykke-AndersenS, ChristensenMS, et al. (2008) RNA exosome depletion reveals transcription upstream of active human promoters. Science 322: 1851–1854.
15. MitchellP, PetfalskiE, ShevchenkoA, MannM, TollerveyD (1997) The Exosome: A Conserved Eukaryotic RNA Processing Complex Containing Multiple 3′→5′ Exoribonucleases. Cell 91: 457–466.
16. BonneauF, BasquinJ, EbertJ, LorentzenE, ContiE (2009) The Yeast Exosome Functions as a Macromolecular Cage to Channel RNA Substrates for Degradation. Cell 139: 547–559.
17. LiuQ, GreimannJC, LimaCD (2006) Reconstitution, Activities, and Structure of the Eukaryotic RNA Exosome. Cell 127: 1223–1237.
18. DziembowskiA, LorentzenE, ContiE, SéraphinB (2007) A single subunit, Dis3, is essentially responsible for yeast exosome core activity. Nat Struct Mol Biol 14: 15–22.
19. LebretonA, TomeckiR, DziembowskiA, SéraphinB (2008) Endonucleolytic RNA cleavage by a eukaryotic exosome. Nature 456: 993–996.
20. BriggsMW, BurkardKTD, ButlerJS (1998) Rrp6p, the Yeast Homologue of the Human PM-Scl 100-kDa Autoantigen, Is Essential for Efficient 5.8 S rRNA 3′ End Formation. Journal of Biological Chemistry 273: 13255–13263.
21. SchneiderC, KudlaG, WlotzkaW, TuckA, TollerveyD (2012) Transcriptome-wide Analysis of Exosome Targets. Molecular Cell 1–12.
22. LaCavaJ, HouseleyJ, SaveanuC, PetfalskiE, ThompsonE, et al. (2005) RNA degradation by the exosome is promoted by a nuclear polyadenylation complex. Cell 121: 713–724.
23. CallahanKP, ButlerJS (2010) TRAMP complex enhances RNA degradation by the nuclear exosome component Rrp6. Journal of Biological Chemistry 285: 3540–3547.
24. SchmidtK, XuZ, MathewsDH, ButlerJS (2012) Air proteins control differential TRAMP substrate specificity for nuclear RNA surveillance. RNA 18: 1934–1945.
25. ChekanovaJA (2000) Poly(A) Tail-dependent Exonuclease AtRrp41p from Arabidopsis thaliana Rescues 5.8 S rRNA Processing and mRNA Decay Defects of the Yeast ski6 Mutant and Is Found in an Exosome-sized Complex in Plant and Yeast Cells. Journal of Biological Chemistry 275: 33158–33166.
26. ListerR, O'MalleyRC, Tonti-FilippiniJ, GregoryBD, BerryCC, et al. (2008) Highly Integrated Single-Base Resolution Maps of the Epigenome in Arabidopsis. Cell 133: 523–536.
27. OnoderaY, HaagJR, ReamT, NunesPC, PontesO, et al. (2005) Plant Nuclear RNA Polymerase IV Mediates siRNA and DNA Methylation-Dependent Heterochromatin Formation. Cell 120: 613–622.
28. HaagJR, PikaardCS (2011) Multisubunit RNA polymerases IV and V: purveyors of non-coding RNA for plant gene silencing. Nature Reviews Molecular Cell Biology 12: 483–492.
29. ChanSWL, ZilbermanD, XieZ, JohansenLK, CarringtonJC, et al. (2004) RNA silencing genes control de novo DNA methylation. Science 303: 1336.
30. ZhengB, WangZ, LiS, YuB, LiuJY, et al. (2009) Intergenic transcription by RNA Polymerase II coordinates Pol IV and Pol V in siRNA-directed transcriptional gene silencing in Arabidopsis. Genes & Development 23: 2850–2860.
31. WierzbickiAT, HaagJR, PikaardCS (2008) Noncoding Transcription by RNA Polymerase Pol IVb/Pol V Mediates Transcriptional Silencing of Overlapping and Adjacent Genes. Cell 135: 635–648.
32. ZilbermanD, CaoX, JacobsenSE (2003) ARGONAUTE4 Control of Locus-Specific siRNA Accumulation and DNA and Histone Methylation. Science 299: 716–719.
33. XieZ, JohansenLK, GustafsonAM, KasschauKD, LellisAD, et al. (2004) Genetic and Functional Diversification of Small RNA Pathways in Plants. PLoS Biol 2: e104 doi:10.1371/journal.pbio.0020104.sg002.
34. ZhengX, ZhuJ, KapoorA, ZhuJ-K (2007) Role of Arabidopsis AGO6 in siRNA accumulation, DNA methylation and transcriptional gene silencing. The EMBO Journal 26: 1691–1701.
35. GaoZ, LiuH-L, DaxingerL, PontesO, HeX, et al. (2010) An RNA polymerase II- and AGO4-associated protein acts in RNA-directed DNA methylation. Nature 465: 106–109.
36. KannoT, BucherE, DaxingerL, HuettelB, BöhmdorferG, et al. (2008) A structural-maintenance-of-chromosomes hinge domain–containing protein is required for RNA-directed DNA methylation. Nat Genet 40: 670–675.
37. KannoT, BucherE, DaxingerL, HuettelB, KreilDP, et al. (2010) RNA-directed DNA methylation and plant development require an IWR1-type transcription factor. EMBO reports 11: 65–71.
38. BühlerM, HaasW, GygiSP, MoazedD (2007) RNAi-Dependent and -Independent RNA Turnover Mechanisms Contribute to Heterochromatic Gene Silencing. Cell 129: 707–721.
39. BühlerM, SpiesN, BartelDP, MoazedD (2008) TRAMP-mediated RNA surveillance prevents spurious entry of RNAs into the Schizosaccharomyces pombe siRNA pathway. Nat Struct Mol Biol 15: 1015–1023.
40. Reyes-TurcuFE, ZhangK, ZofallM, ChenE, GrewalSIS (2011) Defects in RNA quality control factors reveal RNAi-independent nucleation of heterochromatin. Nat Struct Mol Biol 18: 1132–1138.
41. ZofallM, YamanakaS, Reyes-TurcuFE, ZhangK, RubinC, et al. (2012) RNA Elimination Machinery Targeting Meiotic mRNAs Promotes Facultative Heterochromatin Formation. Science 335: 96–100.
42. GazzaniS, LawrensonT, WoodwardC, HeadonD, SablowskiR (2004) A Link Between mRNA Turnover and RNA Interference in Arabidopsis. Science 306: 1046–1048.
43. MiS, CaiT, HuY, ChenY, HodgesE, et al. (2008) Sorting of Small RNAs into Arabidopsis Argonaute Complexes Is Directed by the 5′ Terminal Nucleotide. Cell 133: 116–127.
44. LeeT-F, GurazadaSGR, ZhaiJ, LiS, SimonSA, et al. (2012) RNA polymerase V-dependent small RNAs in Arabidopsis originate from small, intergenic loci including most SINE repeats. Epigenetics 7: 781–795.
45. WierzbickiAT, CocklinR, MayampurathA, ListerR, RowleyMJ, et al. (2012) Spatial and functional relationships among Pol V-associated loci, Pol IV-dependent siRNAs, and cytosine methylation in the Arabidopsis epigenome. Genes & Development 26: 1825–1836.
46. HaagJR, PontesO, PikaardCS (2009) Metal A and metal B sites of nuclear RNA polymerases Pol IV and Pol V are required for siRNA-dependent DNA methylation and gene silencing. PLoS ONE 4: e4110 doi:10.1371/journal.pone.0004110.
47. KasschauKristin D, FahlgrenNoah, ChapmanElisabeth J, SullivanChristopher M, CumbieJason S, et al. (2007) Genome-Wide Profiling and Analysis of Arabidopsis siRNAs. PLoS Biol 5: 1–15.
48. PontierD, YahubyanG, VegaD, BulskiA, Saez-VasquezJ, et al. (2005) Reinforcement of silencing at transposons and highly repeated sequences requires the concerted action of two distinct RNA polymerases IV in Arabidopsis. Genes & Development 19: 2030–2040.
49. GasciolliV, MalloryAC, BartelDP, VaucheretH (2005) Partially Redundant Functions of Arabidopsis DICER-like Enzymes and a Role for DCL4 in Producing trans-Acting siRNAs. Current Biology 15: 1494–1500.
50. HuettelB, KannoT, DaxingerL, AufsatzW, MatzkeAJ, et al. (2006) Endogenous targets of RNA-directed DNA methylation and Pol IV in Arabidopsis. The EMBO Journal 25: 1–9.
51. HerrAJ, JensenMB, DalmayT, BaulcombeDC (2005) RNA Polymerase IV Directs Silencing of Endogenous DNA. Science 308: 118–120.
52. KannoT, HuettelB, MetteMF, AufsatzW, JaligotE, et al. (2005) Atypical RNA polymerase subunits required for RNA-directed DNA methylation. Nat Genet 37: 761–765.
53. MyougaF, TsuchimotoS, NomaK, OhtsuboH, OhtsuboE (2001) Identification and structural analysis of SINE elements in the Arabidopsis thaliana genome. Genes and Genetics systems 76: 169–179.
54. LangeH, HolecS, CognatVE, PieuchotL, Le RetM, et al. (2008) Degradation of a Polyadenylated rRNA Maturation By-Product Involves One of the Three RRP6-Like Proteins in Arabidopsis thaliana. Molecular and Cellular Biology 28: 3038–3044.
55. VasiljevaL, KimM, TerziN, SoaresLM, BuratowskiS (2008) Transcription Termination and RNA Degradation Contribute to Silencing of RNA Polymerase II Transcription within Heterochromatin. Molecular Cell 29: 313–323.
56. Reyes-TurcuFE, GrewalSI (2012) Different means, same end—heterochromatin formation by RNAi and RNAi-independent RNA processing factors in fission yeast. Current Opinion in Genetics & Development 22: 156–163.
57. WangS-W, StevensonAL, KearseySE, WattS, BählerJ (2008) Global role for polyadenylation-assisted nuclear RNA degradation in posttranscriptional gene silencing. Molecular and Cellular Biology 28: 656–665.
58. CamblongJ, IglesiasN, FickentscherC, DieppoisG, StutzF (2007) Antisense RNA stabilization induces transcriptional gene silencing via histone deacetylation in S. cerevisiae. Cell 131: 706–717.
59. HouseleyJ, RubbiL, GrunsteinM, TollerveyD, VogelauerM (2008) A ncRNA modulates histone modification and mRNA induction in the yeast GAL gene cluster. Molecular Cell 32: 685–695.
60. MosherRA, SchwachF, StudholmeD, BaulcombeDC (2008) PolIVb influences RNA-directed DNA methylation independently of its role in siRNA biogenesis. PNAS 105: 3145–3150.
61. HerrAJ, MolnarA, JonesA, BaulcombeDC (2006) Defective RNA processing enhances RNA silencing and influences flowering of Arabidopsis. PNAS 103: 14994–15001.
62. WierzbickiAT, ReamTS, HaagJR, PikaardCS (2009) RNA polymerase V transcription guides ARGONAUTE4 to chromatin. Nat Genet 41: 630–634.
63. AmedeoP, HabuY, AfsarK, ScheldOM, PaszkowskiJ (2000) Disruption of the plant gene wyw releases transcriptional silencing of methylated genes. Nature 405: 203–206.
64. TariqM, HabuY, PaszkowskiJ (2002) Depletion of MOM1 in non-dividing cells of Arabidopsis plants releases transcriptional gene silencing. EMBO reports 3: 951–955.
65. VaillantI, SchubertI, TourmenteS, MathieuO (2006) MOM1 mediates DNA-methylation-independent silencing of repetitive sequences in Arabidopsis. EMBO reports 7: 1273–1278.
66. TakedaShin, TadeleZerihun, HofmannI, ProbstAline V, AngelisKJ, et al. (2004) BRU1, a novel link between responses to DNA damage and epigenetic gene silencing in Arabidopsis. Genes & Development 18: 782–793.
67. ElmayanT, ProuxF, VaucheretH (2005) Arabidopsis RPA2: A Genetic Link among Transcriptional Gene Silencing, DNA Repair, and DNA Replication. Current Biology 15: 1919–1925.
68. BaurleI, SmithL, BaulcombeDC, DeanC (2007) Widespread Role for the Flowering-Time Regulators FCA and FPA in RNA-Mediated Chromatin Silencing. Science 318: 109–112.
69. YokthongwattanaC, BucherE, aikovskiMC, VaillantI, NicoletJEL, et al. (2009) MOM1 and Pol-IV/V interactions regulate the intensity and specificity of transcriptional gene silencing. The EMBO Journal 29: 1–12.
70. LiuF, BakhtS, DeanC (2012) Cotranscriptional Role for Arabidopsis DICER-LIKE 4 in Transcription Termination. Science 335: 1621–1623.
71. MoissiardG, CokusSJ, CaryJ, FengS, BilliAC, et al. (2012) MORC Family ATPases Required for Heterochromatin Condensation and Gene Silencing. Science 336: 1448–1451.
72. HabuY, MathieuO, TariqM, ProbstAV, SmathajittC, et al. (2006) Epigenetic regulation of transcription in intermediate heterochromatin. EMBO reports 7: 1279–1284.
73. SteimerA, AmedeoP, KarinAfsar, FranszP, ScheidOM, et al. (2000) Endogenous Targets of Transcriptional Gene Silencing in Arabidopsis. The plant Cell 12: 1165–1178.
74. ProbstAV, FranszPF, PaszkowskiJ, ScheidOM (2003) Two means of transcriptional reactivation within heterochromatin. THe plant journal 33: 743–749.
75. NumaH, KimJ-M, MatsuiA, KuriharaY, MorosawaT, et al. (2009) Transduction of RNA-directed DNA methylation signals to repressive histone marks in Arabidopsis thaliana. The EMBO Journal 29: 352–362.
76. HollisterJD, GautBS (2009) Epigenetic silencing of transposable elements: A trade-off between reduced transposition and deleterious effects on neighboring gene expression. Genome Research 19: 1419–1428.
77. JullienPE, KinoshitaT, OhadN, BergerF (2006) Maintenance of DNA Methylation during the Arabidopsis Life Cycle Is Essential for Parental Imprinting. The plant Cell 18: 1360–1372.
78. HamiltonA, VoinnetO, ChappellL, BaulcombeD (2002) Two classes of short interfering RNA in RNA silencing. The EMBO Journal 21: 4671–4679.
79. HalicM, MoazedD (2010) Dicer-Independent Primal RNAs Trigger RNAi and Heterochromatin Formation. Cell 140: 504–516.
80. ZhangK, FischerT, PorterRL, DhakshnamoorthyJ, ZofallM, et al. (2011) Clr4/Suv39 and RNA Quality Control Factors Cooperate to Trigger RNAi and Suppress Antisense RNA. Science 331: 1624–1627.
81. BernardP, DrogatJ, DheurS, LongoG, JaverzatJP (2010) Splicing Factor Spf30 Assists Exosome-Mediated Gene Silencing in Fission Yeast. Molecular and Cellular Biology 30: 1145–1157.
82. PontesO, Costa-NunesP, VithayathilP, PikaardCS (2009) RNA Polymerase V Functions in Arabidopsis Interphase Heterochromatin Organization Independently of the 24-nt siRNA-Directed DNA Methylation Pathway. Molecular Plant 2: 700–710.
83. KellerC, AdaixoR, StunnenbergR, WoolcockKJ, HillerS, et al. (2012) HP1Swi6 Mediates the Recognition and Destruction of Heterochromatic RNA Transcripts. Molecular Cell 47: 215–227.
84. ZhangX, GermannS, BlusBJ, KhorasanizadehS, GaudinV, et al. (2007) The Arabidopsis LHP1 protein colocalizes with histone H3 Lys27 trimethylation. Nat Struct Mol Biol 14: 869–871.
85. DouetJ, TutoisS, TourmenteS (2009) A Pol V–Mediated Silencing, Independent of RNA–Directed DNA Methylation, Applies to 5S rDNA. PLoS Genet 5: e1000690 doi:10.1371/journal.pgen.1000690.t001.
86. PontesO, LiCF, NunesPC, HaagJ, ReamT, et al. (2006) The Arabidopsis Chromatin-Modifying Nuclear siRNA Pathway Involves a Nucleolar RNA Processing Center. Cell 126: 79–92.
87. WangH, ZhangX, LiuJ, KibaT, WooJ, et al. (2011) Deep sequencing of small RNAs specifically associated with Arabidopsis AGO1 and AGO4 uncovers new AGO functions. THe plant journal 67: 292–304.
88. FischerSEJ, MontgomeryTA, ZhangC, FahlgrenN, BreenPC, et al. (2011) The ERI-6/7 Helicase Acts at the First Stage of an siRNA Amplification Pathway That Targets Recent Gene Duplications. PLoS Genet 7: e1002369 doi:10.1371/journal.pgen.1002369.g005.
89. ZhengQ, RyvkinP, LiF, DragomirI, ValladaresO, et al. (2010) Genome-Wide Double-Stranded RNA Sequencing Reveals the Functional Significance of Base-Paired RNAs in Arabidopsis. PLoS Genet 6: e1001141 doi:10.1371/journal.pgen.1001141.g007.
90. OlsonAJ, BrenneckeJ, AravinAA, HannonGJ, SachidanandamR (2008) Analysis of large-scale sequencing of small RNAs. Pacific Symposium on Biocomputing 13: 126–136.
91. BlankenbergD, GordonA, Kuster VonG, CoraorN, TaylorJ, et al. (2010) Manipulation of FASTQ data with Galaxy. Bioinformatics 26: 1783–1785.
92. LangmeadB, TrapnellC, PopM, SalzbergSL (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10: R25.
93. QuinlanAaron R, HalIM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26: 841–842.
94. KozomaraA, Griffiths-JonesS (2010) miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Research 39: D152–D157.
95. BensonG (1998) Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Research 27: 573–580.
96. WarburtonPE, GiordanoJ, CheungF, GelfandY, BensonG (2004) Inverted Repeat Structure of the Human Genome: The X-Chromosome Contains a Preponderance of Large, Highly Homologous Inverted Repeats That Contain Testes Genes. Genome Research 14: 1861–1869.
97. Smit A, Hubley R, Green P (1996) RepeatMasker Open-3.0. Available: http://www.repeatmasker.org.
98. MorohashiK, XieZ, GrotewoldE (2009) Gene-specific and genome-wide ChIP approaches to study plant transcriptional networks. Methods Mol Biol 553: 3–12.
99. HaringM, OffermannS, DankerT, HorstI, PeterhanselC, et al. (2007) Chromatin immunoprecipitation: optimization, quantitative analysis and data normalization. Plant Methods 3: 11.
100. TerziLC, SimpsonGG (2009) Arabidopsis RNA immunoprecipitation. THe plant journal 59: 163–168.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2013 Číslo 3
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Fine Characterisation of a Recombination Hotspot at the Locus and Resolution of the Paradoxical Excess of Duplications over Deletions in the General Population
- Molecular Networks of Human Muscle Adaptation to Exercise and Age
- Recurrent Rearrangement during Adaptive Evolution in an Interspecific Yeast Hybrid Suggests a Model for Rapid Introgression
- Genome-Wide Association Study and Gene Expression Analysis Identifies as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis