monaLisaMOtif aNAlysis withLisa

EuropeanBioconductorMeeting2019

DaniaMachlabLukasBurgerMichaelStadler

FriedrichMiescher InstituteforBiomedicalResearch

BackgroundandMotivation

Francois Spitz & Eileen E. M. Furlong (2012) Nature Reviews Genetics

Co-binding

Chromatinremodeling

Blockingrepositioning

Architecturalrole

UsemonaLisa to:• IdentifyEnrichedmotifs• Selectmotifsexplainingobservedchanges

BackgroundandMotivation

GenomeGeneAEnhancer

ATAC-seqCondition1

ATAC-seqCondition2

RNA-seqCondition1

RNA-seqCondition2

PredictedTFBS

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

)

SelectMotifsusingStabilitySelection

Randomizedlassostabilityselection

Meinshausen & Bühlmann (2010) Journal of the Royal Statistical Society

observedlogFC predictedTFBS

LassowithCrossValidation

LassoStabilitySelection

RandomizedLassoStabilitySelection

regularizationparameter

weaknessparameter

truesignal noisesmall𝜆large𝜆

Y

~

X

performregularizedregression

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

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