Competitive target gene regulation bypromoter methylation and miRNAY-h. Taguchi, Chuo University
0. What is miRNA?1. Introduction2. Promoter Methylation3. MiRaGE Method4. Competitive target gene regulation bypromoter me...
0. What is miRNA?・miRNA = microRNA・non-coding RNA・regulate (suppress) target gene expression viaeitherdegradation or trans...
1. IntroductionEpigenetic gene expression regulation iscurrent central topics ingenomics/bioinformatics because ….A) Cell ...
Epigenetic gene regulation =gene expression regulation without modification of DNAsequencesExample・promoter methylation・hi...
2. Promoter Methylation                           Methylated                             promoter                         ...
3. MiRaGE MethodMiRaGE :MiRNA Ranking by Gene Expression                 Promoter Methylation               considered    ...
4. Competitive target gene regulation bypromoter methylation and miRNAResult 1:hyper(heypo)methyaletion ⇔ less(more) regul...
GSE30653Nazor KL, Altun G, Lynch C, Tran H et al.Recurrent variations in DNA methylation in humanpluripotent stem cells an...
Amount of methylation                           Number of casesStatistical tests   Not significant  Significant     t-test...
P-values are highly cell type independentMean Pearsons correlation coefficients of P-value betweenpairs of cell lines. Sta...
Result 2:Genes with hypomethyaled promoter aredownregulated during cell senescence
Result 3:Genes with hypomethyaled promoter areupregulated during differentiation from EScell
IMR90 and MRC5 (cell senescence)BG02 and BG03 (differentiation from ES cell)P-values of miRNA regulation of targe genes ar...
Cell senescence   Pm:methy = Pm> vs. Pm:regul = Pm>                     IMR90     t test           0.33         0.4       ...
Differentiation   Pm:methy = Pm> vs. Pm:regul = 1− Pm<                         BG02     t test              ー0.25         ...
Result 4: Especially, genes with hypomethylated promoters are targeted by miR-548, which is primate-specific and generally...
5. Conclusion ・Promoter methylation is related to miRNA targeting ・Genes with hypo(hyper)methylated promoters are more(les...
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Competitive target gene regulation by promoter methylation and miRNA

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Competitive target gene regulation by promoter methylation and miRNA

  1. 1. Competitive target gene regulation bypromoter methylation and miRNAY-h. Taguchi, Chuo University
  2. 2. 0. What is miRNA?1. Introduction2. Promoter Methylation3. MiRaGE Method4. Competitive target gene regulation bypromoter methylation and miRNA5. Conclusion
  3. 3. 0. What is miRNA?・miRNA = microRNA・non-coding RNA・regulate (suppress) target gene expression viaeitherdegradation or translation interruptionof target genes
  4. 4. 1. IntroductionEpigenetic gene expression regulation iscurrent central topics ingenomics/bioinformatics because ….A) Cell types (development, diseases, tumorformation etc... ) are often decided byepigentic regulationB)Control of epigenetic regulation can altercell types (suppression of cancer, inductionof pluripotency....)
  5. 5. Epigenetic gene regulation =gene expression regulation without modification of DNAsequencesExample・promoter methylation・histon modification・transcription factor binding to promoter region・miRNA regulation of target genes..... How these two regulate gene expression cooperatively is unknown.
  6. 6. 2. Promoter Methylation Methylated promoter ⇓ expression suppression unmethylated promoter ⇓ no expression suppression
  7. 7. 3. MiRaGE MethodMiRaGE :MiRNA Ranking by Gene Expression Promoter Methylation considered miRNA target miRNA gene VS target gene significantly gene up/downregulated? hypo/hypermethylated? (t test, Wilcoxon test, KS test)
  8. 8. 4. Competitive target gene regulation bypromoter methylation and miRNAResult 1:hyper(heypo)methyaletion ⇔ less(more) regulated by miRNAs suppressive suppressive
  9. 9. GSE30653Nazor KL, Altun G, Lynch C, Tran H et al.Recurrent variations in DNA methylation in humanpluripotent stem cells and their differentiatedderivatives.Cell Stem Cell 2012 May 4;10(5):620-34.numbed of cell lines : 271Promoter methylation is measured by microarraymethylation:raw value (raw signal)β-value (normalized value)271 cell lines vs 1921 miRNAs = 520591 casesP-values of miRNA target specific promoterhypomethylation is computed by MiRaGE methodhypoSignificance : adjusted P-value <0.05
  10. 10. Amount of methylation Number of casesStatistical tests Not significant Significant t-test 136054 384537 74%Wilcoxon rank 144572 376019 72% sum test Kolmogorov- 129998 390593 75% Smirnov test β-values Number of casessStatistical tests Not significant Significant t-test 39390 481201 92% Wilcoxon test 45188 475403 91% KS test 41952 478639 92%
  11. 11. P-values are highly cell type independentMean Pearsons correlation coefficients of P-value betweenpairs of cell lines. Statistical test Averaged correlation coefficients Amount of methylation t-test 0.9112043 Wilcoxon rank 0.8981256 sum test Kolmogorov- 0.8263153 Smirnov test β-values t-test 0.8919359 Wilcoxon test 0.8832241 K-Stest 0.8257556
  12. 12. Result 2:Genes with hypomethyaled promoter aredownregulated during cell senescence
  13. 13. Result 3:Genes with hypomethyaled promoter areupregulated during differentiation from EScell
  14. 14. IMR90 and MRC5 (cell senescence)BG02 and BG03 (differentiation from ES cell)P-values of miRNA regulation of targe genes arecomputed by MiRaGE methodCorrelation coefficients between P-vales for promoter hypomethylation and P-values of miRNA downregulation of target genes are computed Hypomethylation : gene expression : expressive vs downregulation of miRNA target genesmiRNA regulation of target genes and promotermethylation are competitive
  15. 15. Cell senescence Pm:methy = Pm> vs. Pm:regul = Pm> IMR90 t test 0.33 0.4 0.41 P -values *(<2E-16) * * Wilcoxon test 0.28 0.35 0.33 P -values * * * K-S test 0.31 0.72 0.61 P -values * * * MRC5 t test 0.22 0.23 0.25 P -values * * * Wilcoxon test 0.53 0.76 0.73 P -values * * * K-S test 0.38 0.82 0.67 P -values * * *
  16. 16. Differentiation Pm:methy = Pm> vs. Pm:regul = 1− Pm< BG02 t test ー0.25 ー0.68 ー0.67 P -values *(<2E-16) * * Wilcoxon test ー0.13 ー0.52 ー0.53 P -values 2.4E-9 * * K-S test ー0.16 ー0.7 ー0.69 P -values 2.8 E-12 * * BG03 t test ー0.31 ー0.57 ー0.53 P -values * * * Wilcoxon test ー0.14 ー0.23 ー0.23 P -values 8.9 E-11 * * K-S test ー0.14 ー0.21 ー0.19 P -values 1.3E-10 * *
  17. 17. Result 4: Especially, genes with hypomethylated promoters are targeted by miR-548, which is primate-specific and generally not expressive miRNAs.Cooperative miRNA regulation with promotermethylation of target gene may assist miRNA-548 to regulate target genes.
  18. 18. 5. Conclusion ・Promoter methylation is related to miRNA targeting ・Genes with hypo(hyper)methylated promoters are more(less) frequently targeted by miRNAs ・miR-548 targeting specific promoter methylation may help miR-548 to regulate target genes.

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