Apparent microRNA-target-specific histone modification in mammalian spermatogenesis
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Presentation at SIGBIO39 Full paper http://www.ncbi.nlm.nih.gov/pubmed/25780334
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Apparent microRNA-target-specific histone modification in mammalian spermatogenesis
- 1. t Apparent microRNA-taarrggeett--ssppeecciiffiicc hhiissttoonnee mmooddiiffiiccaattiioonn iinn mmaammmmaalliiaann ssppeerrmmaattooggeenneessiiss YY--hh.. TTaagguucchhii DDeepptt.. PPhhyyss.. CChhuuoo UUnniivv..
- 2. IInnttrroodduuccttiioonn EEppiiggeenneettiicc rreegguullaattiioonn ooff ggeennee eexxpprreessssiioonn iiss kknnoowwnn ttoo bbee iimmppoorrttaanntt nnoowwaaddaayyss.. ee..gg.. -- DDeevveellooppmmeenntt aanndd CCeelllluullaarr DDiiffffeerreennttiiaattiioonn -- DDiisseeaasseess iinncclluuddiinngg CCaanncceerr -- AAggiinngg
- 3. EExxaammppllee ooff EEppiiggeenneettiicc rreegguullaattiioonn ooff ggeenneess -- TTrraannssccrriippttiioonn FFaaccttoorr BBiinnddiinnggss ttoo pprroommootteerr rreeggiioonn -- HHiissttoonn mmooddiiffiiccaattiioonn -- PPrroommootteerr MMeetthhyyllaattiioonn -- mmiiRRNNAA rreegguullaattiioonn ooff ttaarrggeett ggeenneess.. eettcc.. eettcc.. IInntteerraaccttiioonn RRaarreellyy DDiissccuusssseedd BBootthh ggeennee rreegguullaattiioonn
- 4. cell nucleus miRNA Gene 3'UTR cytoplasm histone modification histone modification ↔ cell nucleus miRNA ↔ cytoplasm
- 5. PPrreevviioouuss RReesseeaarrcchh SSuu eett aall ((22001111,, BBMMCC GGeennoommiiccss)) ““mmiiRRNNAAss tteennddeedd ttoo ttaarrggeett tthhee ggeenneess wwiitthh aa llooww DDNNAA mmeetthhyyllaattiioonn lleevveell iinn tthheeiirr pprroommootteerr rreeggiioonnss”” PPrroommootteerr mmeetthhyyllaattiioonn ↔↔ mmiiRRNNAA ttaarrggeettiinngg PPuurrppoossee ooff mmyy ssttuuddyy:: HHiissttoonnee mmooddiiffiiccaattiioonn iiss mmiiRRNNAA--ttaarrggeettiinngg--ssppeecciiffiicc oorr nnoott?? ((IInn ootthheerr wwoorrddss,, hhiissttoonnee mmooddiiffiiccaattiioonn iiss aaffffeecctteedd bbyy bbeeiinngg ttaarrggeetteedd bbyy iinnddiivviidduuaall mmiiRRNNAA oorr nnoott??))
- 6. MiRaGE Method MiRaGE : MiRNA Ranking by Gene Expression Histone modification significantly up/downregulated? (t test, Wilcoxon test, KS test) miRNA target gene target gene VS considered miRNA gene modified histone?
- 7. My Previous Results “Substantial number of miRNAs have target genes with significantly hyper/hypomethylated promoters” References: - Y-h. Taguchi (2012) IPSJ SIG Tech. Rep. 2012-BIO-31(1) pp.1-6 - Y-h. Taguchi, (2013) F1000Research [v1; ref status: approved 1, not approved 2, http://f1000r.es/wv]
- 8. This Study Comparison between miRNA and histone modification during spermatogenesis in miRNA-centric manner. NGS: Spermatogonia(SG)→Spermatocytes(SC)→ Spermatids(ST) vs Controls H3K4me1, H3K27me3, H3K4me3, H3K27ac, H2AZ
- 9. Calculation - Many miRNAs with significant (*) histone modification among multiple miRNAs for all SC, ST, SG vs Controls (*) BH adjusted P <0.05 SG SC SG ST ST SC
- 10. less modificated more modificated Differenciation
- 11. Clustering using negative signed correlation Cluste coefficient of PP--vvaalluueess Biologically feasible
- 12. Clustering using negative signed correlation coefficient of llooggaarriitthhmmiicc rraattiioo Less biologically feasible
- 13. P-values computed by MiRaGE are more biologically feasible than raw values (logarithmic ratio)
- 14. Selected miRNAs are biologically rreeaassoonnaabbllee less modificated hsa- more modificated hsa- Stemness Mouse ES cell specific ↑during differentiation hsa- Critical roles in spermatogenesis Sperm abnormaly hsa- Expressed in abnormal semen
- 15. Is it artifact ? → No, since essentially nnoo mmiiRRNNAAss wwiitthh ssiiggnniiffiiccaanntt hhiissttoonnee mmooddiiffiiccaattiioonn aafftteerr ggeennee sshhuufffflliinngg less modificated more modificated
- 16. Samples → Test 2 mRNA(gene) → Simultaneous shuffling with keeping correlation coefficients of logarithmic ratio
- 17. Clustering using negative signed correlation coefficient of PP--vvaalluueess after simultaneous shuffling More similar to cluster obtained by raw values (logarithmic ratio)
- 18. Thus, converting logarithmic ratio to P-values by MiRaGE enphances biological feasibility
- 19. Human sperm exhibits similar miRNA specific histone modification less modificated more modificated
- 20. Too simple model? → comparison wwiitthh llaassssoo Predicted activity of k th miRNA differential expression of i th mRNA and j th histone modification 11 if k th miRNA targets ith mRNA 00 otherwise
- 21. βk P-values
- 22. MiRaGE is well coincident with lasso. Thus, biological feasibilities obtained by miRNA specific histone modification will not be likely fake.
- 23. CCoonncclluussiioonnss ・P-values computed by MiRaGE are highly tissue/histone modification specific. ・ Most significant miRNAs are stem cell or sperm specific. Thus, biologically feasible. ・Since gene order shuffling destroys miRNA specific significant histone modification, it is not an artifact. ・Since it is coincident with lasso, biological feasibility is not due to too simple algorithm ・Biological mechanism that causes miRNA specific histone modification should be cleared.