monaLisa MOtifaNAlysiswith Lisaeurobioc2019.bioconductor.org/slides/.../monaLisa... · monaLisa...
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monaLisaMOtif aNAlysis withLisa
EuropeanBioconductorMeeting2019
DaniaMachlabLukasBurgerMichaelStadler
FriedrichMiescher InstituteforBiomedicalResearch
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BackgroundandMotivation
Francois Spitz & Eileen E. M. Furlong (2012) Nature Reviews Genetics
Co-binding
Chromatinremodeling
Blockingrepositioning
Architecturalrole
UsemonaLisa to:• IdentifyEnrichedmotifs• Selectmotifsexplainingobservedchanges
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BackgroundandMotivation
GenomeGeneAEnhancer
ATAC-seqCondition1
ATAC-seqCondition2
RNA-seqCondition1
RNA-seqCondition2
PredictedTFBS
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IdentifyEnrichedMotifs
CTC
FC
TCFL
RAR
Avar
2R
arbv
ar2
KLF4 Klf1
Klf1
2E2
F7BH
LHE4
1KL
F13
ZEB1
ERG
ETS1
ETV5
ELK3
ETV1
ETV4
FEV
FLI1
ERF
ETV3 ID
4KL
F14
SP4
enric
hmen
t (lo
g2)
FDR
(−lo
g10)
Perc
ent G
+C
020406080100
log2
enr
ichm
ent
−2−1012
FDR 0246810de
lta
methylatio
n
densityofpromoters
enrichm
ent(log2)
FDR(-log10
)
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SelectMotifsusingStabilitySelection
Randomizedlassostabilityselection
Meinshausen & Bühlmann (2010) Journal of the Royal Statistical Society
observedlogFC predictedTFBS
LassowithCrossValidation
LassoStabilitySelection
RandomizedLassoStabilitySelection
regularizationparameter
weaknessparameter
truesignal noisesmall𝜆large𝜆
Y
~
X
performregularizedregression
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SelectMotifsExplainingObservedChangesinAccessibility
glmnet::glmnet and stabs::stabsel used
NFATC1
TEAD2
TEAD3
NKX2−8
Nkx2−5(var.2)
NFIC
KLF5
GATA3
Gata1
GATA1::TAL1
HNF1A
Nr2f6
Hnf4a
NFATC
1
TEAD
2
TEAD
3
NKX
2−8
Nkx2−5(var.2)
NFIC
KLF5
GATA3
Gata1
GATA1::TAL1
HNF1A
Nr2f6
Hnf4a
Pear. Cor.
−1−0.500.51
1.0
0.8
0.6
0.4
0.2
0.0
sele
ctio
n pr
obab
ility
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SummaryandOutlook
• WecanidentifyTFsenrichedinregionsofinterestthatdisplaycertainlog-foldchanges• WecanselectTFsthatarelikelytoexplaintheobservedlog-foldchangesusingstabilityselection
• Wecanbeuseanyfold-changedefinedonregionsofinterest(ATAC-seq,methylation,expression,ChIP-seq …)toselectmotifsexplainingtheobservedlogFC
• Wewanttolookatmotifenrichmentwithoutusingexistingdatabases(unbiasedview)• Enrichedk-mers,groupingthem,aligningthemtopredictthemotif• SubmittoBioconductor
• https://github.com/fmicompbio/monaLisa