human micrornas co-silence in well-separated groups and have different essentialities gábor boross,...

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