human micrornas co-silence in well-separated groups and have different essentialities gábor boross,...
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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)
• 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
Short regulatory RNAs: Pathways and targets
He et.al. 2004 Science
Control of protein concentrations by transcription factor proteins and ncRNAs
Hobert et.al. 2008 Science
Control of protein concentrations by transcription factor proteins and ncRNAs
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
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)
Modules of co-silencing miRNAs are well separated
Seed sequence variation within and between co-regulating modules of miRNAs
Seed match: best indicator of interaction(Lewis et.al, 2003)
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)
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)
Essentiality of human miRNAs: A network property with two networks: co-regulation & co-expression
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
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
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
Co-regulation scores, modules and essentialities extract high-confidence information from miRNA-target scores
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
Predicted (relative) essentialities of human miRNAs
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
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