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![Page 1: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/1.jpg)
Human microRNAs co-silence in well-separated groups and have different essentialities
Gábor Boross, Katalin Orosz, Illés J. FarkasEotvos University and Hung. Acad. of Sci., Budapest, Hungary
Nov, 2008Support: Hungarian Sci. Res. Fund (OTKA) Hung. National Office for Res. and Techn. (NKTH)
![Page 2: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/2.jpg)
• Short regulatory RNAs
• RNA silencing vs. transcription regulation
• Databases listing miRNA – target pairs: huge differences
• With growing sample size: increasing similarity
• Baek et.al., Selbach et.al (2008) use TargetScan (and PicTar)
• Modules of co-silencing miRNAs are well separated
• Example: Seed sequence variation within and between co-regulating modules of miRNAs
• Application: Essentiality of human miRNAs
• Data filtering: Co-regulation modules, essentialities: more reliable than miRNA-target scores
• Well-separated modules, “group-to-group control”
• may explain low number of individually essential miRNAs (Miska et.al. 2008)
• Essentiality of miRNAs is a network property: position within a module
• may explain large role of ubiquitously expressed miRNAs (Landgraf et.al. 2008)
• Computational prediction: Group of 9 most vs. 6 least essential miRNAs lethality
![Page 3: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/3.jpg)
Short regulatory RNAs: Pathways and targets
He et.al. 2004 Science
![Page 4: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/4.jpg)
Control of protein concentrations by transcription factor proteins and ncRNAs
Hobert et.al. 2008 Science
![Page 5: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/5.jpg)
Control of protein concentrations by transcription factor proteins and ncRNAs
![Page 6: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/6.jpg)
Computationally predicted lists of miRNA-target pairs differ strongly
Example from C.elegans:Computationally predicted relative strength of two well-known miRNA-target interactions
miRBase PITA PicTar TargetScan
lin-4 - LIN-14 No No Yes: 11.20 Yes
let-7 - LIN-41 Yes Yes Yes: 4.18 No
![Page 7: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/7.jpg)
With growing sample size computationally predicted interaction lists become increasingly similar
(1) No benchmark data set
(2) Baek et.al., Selbach et.al. (2008):
TargetScan & PicTar can most precisely predictmessenger RNA and protein level fold changesupon the insertion / removal of selected miRNAs
use TargetScan (control: PicTar)
![Page 8: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/8.jpg)
Modules of co-silencing miRNAs are well separated
![Page 9: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/9.jpg)
Seed sequence variation within and between co-regulating modules of miRNAs
Seed match: best indicator of interaction(Lewis et.al, 2003)
![Page 10: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/10.jpg)
Seed sequence variation within and between co-regulating modules of miRNAs
AGCAGCG (miR-503) AGCAGCA (all others)
purine (A) purine (G) at last residue
Seed match: best indicator of interaction(Lewis et.al, 2003)
![Page 11: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/11.jpg)
Seed sequence variation within and between co-regulating modules of miRNAs
AGCAGCG (miR-503) AGCAGCA (all others)
purine (A) purine (G) at last residue
AGCACCA
purine (G) pyrimidine (G) inside seed
Seed match: best indicator of interaction(Lewis et.al, 2003)
![Page 12: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/12.jpg)
Essentiality of human miRNAs: A network property with two networks: co-regulation & co-expression
![Page 13: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/13.jpg)
let-7a is co-expressed with the miRNAs that it co-regulates with
Essentiality of human miRNAs: A network property with two networks: co-regulation & co-expression
![Page 14: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/14.jpg)
let-7a is co-expressed with the miRNAs that it co-regulates with
let-7g is not co-expressed with the miRNAs that it co-regulates with
Essentiality of human miRNAs: A network property with two networks: co-regulation & co-expression
![Page 15: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/15.jpg)
let-7a is co-expressed with the miRNAs that it co-regulates with
let-7g is not co-expressed with the miRNAs that it co-regulates with
Knock-out: let-7g vs. let-7a
If let-7g is knocked out, then its functions can be replaced with much smaller precision ( = bigger errors )
let-7g is more essential then let-7aNot co-expressed with co-regulating partners
Essentiality of human miRNAs: A network property with two networks: co-regulation & co-expression
![Page 16: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/16.jpg)
Co-regulation scores, modules and essentialities extract high-confidence information from miRNA-target scores
![Page 17: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/17.jpg)
Discussion
Group-to-group control
miRNA group: each miRNA silences almost the same set of target genes
may explain low number of individually essential miRNAs in C.elegans (Miska et.al. 2008)
Essentiality of miRNAs is a network property
position within a module: differently expressed from strongly co-regulating other miRNAs
may explain large role of ubiquitously expressed miRNAs (Landgraf et.al. 2008)
Data filtering
6 (9) out of 10 most (least) essential miRNAs with TargetScan vs. PicTar data are identical
Computational prediction: Experimentally testable hypotheses
List of individually most and least essential human miRNAs
![Page 18: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/18.jpg)
Predicted (relative) essentialities of human miRNAs
![Page 19: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/19.jpg)
Human microRNAs co-silence in well-separated groups and have different essentialities
Gábor Boross, Katalin Orosz, Illés J. FarkasEotvos University and Hung. Acad. of Sci., Budapest, Hungary
![Page 20: Human microRNAs co-silence in well-separated groups and have different essentialities Gábor Boross, Katalin Orosz, Illés J. Farkas Eotvos University and.](https://reader036.fdocuments.us/reader036/viewer/2022062422/56649f305503460f94c4a9c1/html5/thumbnails/20.jpg)
Human microRNAs co-silence in well-separated groups and have different essentialities
Gábor Boross, Katalin Orosz, Illés J. FarkasEotvos University and Hung. Acad. of Sci., Budapest, Hungary
Support: Hungarian Sci. Res. Fund (OTKA) Hung. National Office for Res. and Techn. (NKTH)
Nov, 2008