Library of Integrated Network Based Cellular Signatures (LINCS)

26 Pages·2014·1.81 MB·English

by  Aravind Subramanian

Library of Integrated Network Based
Cellular Signatures
(LINCS)
Aravind Subramanian
NIEHS Workshop
June 26, 2013
LINCS as a look-up table of cellular activity
database
COMMUNITY
QUERIES
PLATFORM-
INDEPENDENT
GENOME SCALE MODERATE
GENETIC COMPLEXITY
PHARMACOLOGIC 10’S COMPLEX
read out
perturbations cell types
Connectivity Map
diseases genes drugs
mRNA Expression Database
453 Affymetrix profiles

164 drugs

> 16,000 users

Lamb et al, Science (2006)
916 citations
Expanding the Connectivity Map Concept
more small molecules
drugs, tools, natural products, libraries
genomic perturbations
shRNA, ORF, variants
cellular contexts
cell types, culture conditions
treatment parameters
concentrations, durations, combinations
At ~ $500/array, approach does not scale
Toward reduced representation of transcriptome

gene expression is correlated
samples
LINCS
s
e
n
e
g
Reduced Representation of Transcriptome
reduced

computational genome-wide
representation
inference model expression profile

transcriptome
‘landmarks’
100

80%80
simulation

s
~ 130,000 profiles
n 60
o
i
t
c
40
e
n
n
o 20
c

%
0
83 12 00 00 00 00
000 00 00 00 00
2 8 0 0 0 5 00 7 5 3 1
2 4 0 5 2 1 1
2 1 1 0
1
number of landmarks measured
1000-plex Luminex bead profiling
5' 3'
AAAA
 RT
5' 3'
5'-PO
4

|
Luminex Beads
3'
TTTT (500 colors,
2 genes/color)
 ligation
5'
5'
 PCR
 hybridization
Reagent cost:
$5/sample
001
LINCS Goal
Current LINCS Dataset
small-molecules genomic perturbagens
1,000 landmark genes 1,209,824 profiles
21,000 inferred genes
5,178 compounds
• 1,300 off-patent FDA-approved drugs
15 cell types
• 700 bioactive tool compounds
• Banked primary cell types
• 2,000+ screening hits (MLPCN + others)
• Cancer cell lines
3,712 genes (shRNA + cDNA)
• Primary hTERT­
immortalized •targets/pathways of FDA-approved drugs
• Patient-derived iPS cells (n=900)
• 5 community nominated •candidate disease genes (n=600)
it iti ( 500 )
cell types

p 300 CTD2 cmpds x 50 cell lines

e
r
t
u
r
b
a
t
i
o
n
s

10,000 DOS compounds x 5 cell lines