FOS like 1, AP-1 ansc ip ion ac o subuni (FOSL1) :
Time beha iou al s udy o 3 d o de combina ions in
WNT3A s imula ed HEK 293 cells
sh ip akash sinha
Independen Resea che ; O cid ID : o cid.o g/0000-0001-7027-5788
104-Madhu isha Heigh s Phase 1, Risali, Bhilai-490006, India
Abs ac
FOSL1 is one o he ou membe s o he FOS gene amily. These genes encode
leucine zippe p o eins ha can dime ize wi h p o eins o he JUN amily, he eby
o ming he ansc ip ion ac o complex AP-1. FOS p o eins ac as egula o s o cell
p oli e a ion, di e en ia ion, and ans o ma ion. Guj al and MacBea h [1] p o ides a
quan i a i e, and dynamic s udy o WNT3A-media ed s imula ion o HEK 293 cells,
whe e hey eco d ime based exp ession p o iles o se e al esponse genes which co -
ela ed signi ican ly wi h p oli e a ion and mig a ion. By moni o ing he dynamics o
gene exp ession using sel -o ganizing maps, hey iden i ied clus e s o genes ha ex-
hibi simila exp ession dynamics and unco e ed p e iously un ecognized posi i e and
nega i e eedback loops. Howe e , hei s udy depic s/uses singula measu emen s o
indi idual gene exp ession a di e en ime snapsho s/poin s o in e he sys em wide
analysis o he pa hway. A any pa icula ime poin , i is o en he case ha genes
a e wo king syne gis ically in combina ions, e en hough hei exp ession measu e-
men s a e singula in na u e. He e, I •enume a e and ank all 2415 FOSL1 ela ed
3 d o de combina ions in a o es o 71C3combina ions using ou di e en sensi i i y
me hods; •show he conse ed ankings o FOSL1-X-X combina ions, which poin
o exis ence o biological syne gy o some o hese combina ions ac oss he di e en
sensi i i y me hods; and •s udy he beha iou o some o hese combina ions ela ed o
WNT3A esponse genes ha a e anked by he machine lea ning sea ch engine (Sinha
[2]) in ime. Pa e ns o combina ions eme ge, some o which ha e been es ed in we
lab, while o he s equi e u he we lab analysis.
Keywo ds: Sensi i i y analysis, Suppo ec o anking, Hilbe Schmid
Independence C i e ion indices (HSIC) and Sobol indicies, WNT3A
ITime beha iou al s udy o 3-od FOSL1 comb. in WNT3A s imula ed cells
Email add ess: [email p o ec ed] (sh ip akash sinha)
1Aspec s o unpublished wo k we e p esen ed in a pos e session a Cell Symposia: Technology. Biology.
Da a Science, 9-11 Oc obe 2016, Be keley, Cali o nia, USA.
P ep in submi ed o P ep in Feb ua y 25, 2025
1. Signi icance
Sinha [2] ecen ly demons a ed he use o machine lea ning based sea ch engine o
ank/ e eal gene combina ions a 2nd o de o he ime se ies da a by Guj al and
MacBea h [1] and showed how i is possible o loca e combina ions o p io i y ha
migh be wo king syne gis ically, using sensi i i y me hods and powe ul suppo ec-
o anking algo i hm. Howe e , he p oblem explodes combina o ially wi h e en a
small se o 71 eco ded genes in he s udy by Guj al and MacBea h [1], when one
s eps o explo e 3 d o de combina ions. Wi h he o al numbe o 71C3(= 57155) com-
bina ions, i becomes nea ly impossible o any biologis o s udy he sys em wide dy-
namics o any pa hway. Also, he amoun o ime usually needed o sea ch o and es
a combina ion is a mo e han he sea ch down by he machine lea ning based sea ch
engine. He e, I ex end he esea ch wo k by Sinha [2] o conduc a beha io al s udy o
3 d o de FOSL1 ela ed combina ions using indi idual gene exp essions measu ed in
ime, in WNT3A s imula ed HEK 293 cells.
2. In oduc ion
The de ails o he machine lea ning based sea ch engine has been ecen ly published in
Sinha [2] and deployed o explo e he 2nd o de combina ions o genes in he da a se
p o ided by Guj al and MacBea h [1]. Ne e heless, he e, I poin o he undamen als
o he published wo k o comple eness.
2.1. A combina o ial p oblem
Sensi i i y analysis plays a majo ole in compu ing he s eng h o he in luence o
in ol ed ac o s in any phenomena unde in es iga ion. When applied o exp ession
p o iles o a ious in a/ex acellula ac o s ha o m an in eg al pa o a signaling
pa hway, he a iance and densi y based analysis yields a ange o sensi i i y indices
o indi idual as well as a ious combina ions o ac o s. These combina ions deno e
he highe o de in e ac ions among he in ol ed ac o s. Compu a ion o highe o -
de in e ac ions is o en ime consuming bu i gi es a chance o explo e he a ious
combina ions ha migh be o in e es in he wo king mechanism o he pa hway. Fo
example, in a ange o ou h o de combina ions among he a ious ac o s o he Wn
pa hway, i would be easy o assess he in luence o he des uc ion complex o med by
APC, AXIN, CSKI and GSK3 in e ac ion. Bu he e ec o hese combina ions a y
o e ime as measu emen s o old changes and de ia ions in old changes a y. So
i is impe a i e o know how an in e ac ion o a combina ion o he in ol ed ac o s
beha e in ime and Sinha [2] de elops a p ocedu e o ack he beha iou by exploi ing
he in luences o hese in ol ed ac o s.
2.2. A possible solu ion
In his wo k, a e es ima ing he indi idual e ec s o ac o s o a highe o de combi-
na ion, he indi idual indices a e conside ed as disc imina i e ea u es. A combina ion,
2
hen, is a ea u e se in highe o de (≥2 ,i.e mul i a ia e). Wi h an excessi ely la ge
numbe o ac o s in ol ed in he pa hway, i is di icul o sea ch o impo an com-
bina ions in a wide sea ch space o e di e en o de s. Exploi ing he analogy wi h
he issues o p io i izing webpages using anking algo i hms, o a pa icula o de , a
ull se o combina ions o in e ac ions can hen be p io i ized based on hese ea u es
using a powe ul anking algo i hm ia suppo ec o s Joachims [3]. Reco ding he
changing ankings o he combina ions o e ime e eals how highe o de in e ac ions
beha e wi hin he pa hway and when an in e en ion migh be necessa y o in luence
he in e ac ion wi hin he pa hway.
2.3. FOS like 1, AP-1 ansc ip ion ac o subuni (FOSL1)
FOSL1 (alias Fos- ela ed an igen 1 o FRA-1), is one o he ou membe s o he FOS
gene amily. Ma sui e al. [4] isola ed cDNA clones o human FRA-1/2 by sc eening
human c-DNA lib a ies wi h human os DNA as a p obe. They ob ained human FRA-1
cDNA clones ha could code o a p o ein o 271 amino acid esidues wi h a calcula ed
molecula weigh o 29,413 and showed 90% simila i y wi h a FRA-1 p o ein. FOSL1
(FRA-1) encodes leucine zippe p o eins ha can dime ize wi h p o eins o he JUN
amily, hus o ming he ansc ip ion ac o complex AP-1.
The basic leucine zippe domain (bZIP domain) is ound in many DNA binding
euka yo ic p o eins, one pa o which media es sequence speci ic DNA binding p op-
e ies and he leucine zippe ha is equi ed o hold oge he (dime ize) wo DNA
binding egions (Ellenbe ge [5] and Vinson e al. [6]). The human me allo hionein
IIa (hMTIIA) gene esponds o induc ion by hea y me als and by s e oid ho mones
h ough he ac ion o me al egula o y elemen s (MRE) and glucoco icoid esponsi e
elemen s (GRE). Lee e al. [7] epo he iden i ica ion o wo cellula DNA-binding
p o eins ha in e ac selec i ely wi h sequences go e ning he basal le el exp ession
o hMTIIA, one o which is a no el ac i a o p o ein (AP-1) ha in e ac s wi h se-
quences in he basal le el enhance (BLE) o hMTIIAand also binds o a si e wi hin he
72-base pai (bp) epea s o he simian i us 40 (SV40) enhance egion. The s uc u e
o AP-1 is a he e odime composed o p o eins belonging o he c-Fos, c-Jun, ATF and
JDP amilies and he AP-1 amily consis s o se e al bZIP domain p o eins, he Jun,
he Fos, and he ATF sub amilies, which all ha e o dime ize be o e hey can bind o
hei DNA a ge si es (Wagne [8]). The nuclea ansc ip ion ac o AP-1, con ols
cellula e en s including cell ans o ma ion, p oli e a ion, di e en ia ion and apop o-
sis (Ameya e al. [9]). Pognonec e al. [10] ound ha FRA-1 in e ac ed wi h USF
(a basic-helixloophelix-leucine zippe (bHLHZip) p o ein). Exp ession o exogenous
USF led o a dec ease in AP-1 dependen ansc ip ion in F9 cells and co-exp ession o
exogenous FRA-1 es o ed he AP-1 ac i i y in a dose-dependen manne .
FRA-1 seems o play a ole in he p og ession o many ca cinomas and FRA-1 o e -
exp ession enhances he mo ili y and in asion o b eas and colo ec al cance cells, bu
inhibi s he umou igenici y o ce ical ca cinoma cell lines (Milde-Langosch [11]). In
his esea ch wo k, I p esen 3 d o de combina ions o FOSL1 wi h o he genes, ha
he machine lea ning based sea ch engine poin s o, as possible syne gis ic combina-
ions ha migh be wo king in ime.
3
3. Me hods
Please e e o sec ions o Sinha [2] o me hods, design o s udy and analysis o da a
o 2nd o de combina ions. The same me hod and design o s udy is used o gene a e
esul s o 3 d o de combina ions p esen ed in his s udy.
4. Time se ies da a
Guj al and MacBea h [1] p esen a se o 71 WNT- ela ed gene exp ession alues o 6
di e en imes poin s o e a ange o 24-hou pe iod using qPCR. The changes ep e-
sen he old-change in he exp ession le els o genes in 200 ng/mL WNT3A-s imula ed
HEK 293 cells in ime ela i e o hei le els in uns imula ed, se um-s a ed cells a 0-
hou . Guj al and MacBea h [1] s a e ha qPCR da a a e he means o h ee biological
eplica es. Only genes whose mean ansc ip le els changed by mo e han wo- old a
one o mo e ime poin s du ing he 24-hou ime cou se we e conside ed signi ican .
Posi i e (nega i e) numbe s ep esen up (down) - egula ion. We ha e al eady co e ed
he issues ela ed o hese da a se s in de ail in Sinha [12]. Reade s a e eques ed o
go h ough hem in he poin ed e e ence. The ools o s udy which a e used he e ha e
been published in ano he ounda ional wo k in Sinha [12].
5. Design o expe imen
5.1. Pipeline o ime se ies da a
Fo he case o ime se ies da a, in e ac ions among he con ibu ing ac o s a e s udied
by compa ing iple s o old-changes a single ime poin s. The p odecu e begins wi h
he gene a ion o dis ibu ion a ound measu emen s a single ime poin s wi h added
noise is done o es ima e he indices. A dis ibu ion is gene a ed o he old changes
a single ime poin s. Then o e e y gene, he e is a ec o o alues ep esen ing old
changes as well as de ia ions in old changes o di e en ime poin s and du a ions
be ween ime poin s, espec i ely. Nex a lis ing o all Cn
kcombina ions o knumbe
o genes om a o al o ngenes is gene a ed. kis ≥2 and ≤(n−1). Each o he com-
bina ion o o de k ep esen s a unique se o in e ac ion be ween he in ol ed gene ic
ac o s. A e his, he da ase s a e combined in a speci ed o ma which go as inpu
as pe he equi emen o a pa icula sensi i i y analysis me hod. Thus o each p h
combina ion in Cn
kcombina ions, he da ase is p epa ed in he equi ed o ma om
he dis ibu ions o wo sepa a e cases which ha e been discussed abo e. (See .R code
in mainSc ip -1-1.R). A e he da a has been ans o med, ec o ized p og amming
is employed o densi y based sensi i i y analysis and looping is employed o a i-
ance based sensi i i y analysis o compu e he equi ed sensi i i y indices o each o
he pcombina ions. This p ocedu e is done o di e en kinds o sensi i i y analysis
me hods.
A e he abo e sensi i i y indices ha e been s o ed o each o he p h combina-
ion, he nex s ep in he design o expe imen is conduc ed. Since he e is only one
4
eco ding o sensi i i y index pe combina ion, each combina ion o ms a aining ex-
ample which is allo ed a aining index and he sensi i i y indices o he indi idual
gene ic ac o s o m he aining example. Thus he e a e Cn
k aining examples o k h
o de in e ac ion. Using his aining se SVMRank
lea n Joachims [3] is used o gene a e a
model on de aul alue C alue o 20. In he cu en expe imen on oy model C alue
has no been unned. The aining se helps in he gene a ion o he model as he di -
e en gene combina ions a e numbe ed in o de which a e used as ank indices. The
model is hen used o gene a e sco e on he obse a ions in he es ing se using he
SV MRank
classi y Joachims [3]. No e ha due o a ailabili y o only one example pe com-
bina ion, a e he model has been buil , he same aining da a is used as es da a o
gene a es he sco es. This p ocedu e is execu ed o each and e e y sensi i i y analysis
me hod. This is ollowed by so ing o hese sco es along wi h he ank indices (i.e he
aining indices) al eady assigned o he gene combina ions. The end esul is a so ed
o de o he gene combina ions based on he anking sco e lea ned by he SV MRank
algo i hm. Finally, his en i e p ocedu e is compu ed o sensi i i y indices gene a ed
o each and e e y old change a ime poin and de ia ions in old change a di e en
du a ions. Obse ing he changing ank o a pa icula combina ion a di e en imes
and di e en ime pe iods will e eal how a combina ion is beha ing.
No e ha he ollowing is he o de in which he iles should be execu ed in R, in
o de , o ob aining he desi ed esul s (No e ha he code will no be explained he e) - •
use sou ce(”mainSc ip -1-1.R”) wi h a gumen s o Dynamic da a •sou ce(”SVMRank-
Resul s-D.R”), o ank he in e ac ions (again his needs o be done sepa a ely o
di e en kinds o SA me hods), •use sou ce(”Combine-Time- iles.R”), i compu -
ing indices sepa a ely ia p e ious ile, •sou ce(”So -n-Plo -D.R”) o so he in e -
ac ions. No e ha he so ing is chages he in e ac ion anking in ime. Thus •use
sou ce(”In e ac ion-P io i y-In ime.R”) o ind he p io i ized anking o each and e -
e y in e ac ion o e he di e en ime poin s and inally •use sou ce(”P in -Ranking-
AND-In e ac ion-Rank.R”) o p in indi idual anking o he equi ed inpu ac o wi h
o he in e ac ion ac o s.
6. Resul s & Discussion
6.1. Time se ies da a by Guj al and MacBea h [1]
NOTE - Ranking was assigned on sco es ha we e so ed in DECREASING alues.
So, 1 was assigned o highes sco e and ice e sa.
Resul s o he 3 d o de in e ac ions a e p esen ed he e. The esul s i s discuss
he beha iou o in e ac ions ac oss he snapsho s o ime using he compu ed sensi-
i i ies on old change measu emen s pe ime snapsho . The analysis was done us-
ing 4 di e en sensi i i y indices. Ou o he 71C3combina ions, I conside /p esen
only hose combina ions ha show a anking wi hin i s 10,000 ou o 57,155. This
choice is libe al and biologis s/oncologis s can ha e a mo e s ic e choice as pe need.
Two obse a ions a e made, • he anking o a pa icula combina ion is conse ed (i.e
wi hin he 10,000 ange) in a pa icula ime poin o in he ea ly phase o la e phase
o WNT3A s imula ion, ac oss he majo i y o he ou sensi i i y me hods, which is a
5
s ic c i e ia o assessmen o • he anking o a pa icula combina ion is conse ed
ac oss ime poin s/phase (i.e hey a e wi hin he 10,000 ange) and he majo i y o he
ou sensi i i y me hods, which is elaxed c i e ia o assessmen . Applying his il e
helps e eal impo an combina ions o in e es ha migh be wo king syne gis ically
a a highe o de le el in he cell.
Rega ding echnical poin s o implemen a ion, he ankings we e gene a ed wi h-
ou scaling/no malizing he ime se ies da a p o ided by Guj al and MacBea h [1].
Fo es ima ing he sensi i i y indices, a small gaussian dis ibu ion using he unc ion
no m ha gene a es a ec o o no mally dis ibu ed andom a iables gi en a ec o
leng h n (he e 9, he 10 h one is he mean/ eco ded gene egula ion i sel ), a popula ion
mean µand popula ion s anda d de ia ion σ. The syn ax o using no m is as ollows:
no m(n, mean, sd). Fu he , I use he ji e un ion o add a li le bi o noise o he
da a. This helps o see i he gene a ed ankings a e obus o no .
6.2. Enume a ion and anking o 2415 FOSL1-X-X combina ions
om Guj al and MacBea h [1]
In he supplemen a y sec ion, I p esen ou iles, each con aining he ankings o 3 d
o de combina ions, ha wa y in ime (shown o 5 ime poin s). Each ile ep esen s
he ankings compu ed using a pa icula sensi i i y me hod. The changing ankings
in ime o a pa icula combina ion ep esen s he impo ance o con ibu ion/ ole ha
combina ion plays in he cell s imula ed wi h WNT3A. The sensi i i y me hods used
a e Hilbe Schmid Independence C i e ion indices (HSIC) indices (wi h b and linea
ke nel in Da Veiga [13]) and Sobol indicies (wi h 2002 implemen a ion in Sal elli [14]
and ma inez implemen a ion in Ma inez [15] and Baudin e al. [16]).
6.3. Conse ed machine lea ning ankings o es ed FOSL1-X-X
combina ions
A o al o 2415, 3 d o de combina ions in ol ing FOSL1 we e ob ained om a ull se
o 71C3= 57155 combina ions. Fu he , om his selec ed se , using he abo e c i e ia
o conse ed ankings, I epo / abula e he meaning ul combina ions ha migh be
wo king syne gis ically. Tables 2, 3 and 4 show he ankings o he same combina-
ions as in able 1, bu using b ke nel o HSIC, 2002 implemen a ion o SOBOL
and ma inez implemen a ion o SOBOL, espec i ely. As one allies he ankings o
ac oss hese ables o a pa icula combina ion, one inds ha he ole o he combina-
ion o in e es is conse ed. This conse a ion poin s o he exis ence o he biological
syne gy, whe he he combina ion has been es ed o unexplo ed/un es ed.
6.3.1. Examining he beha iou o JUN-FOSL1-X combina ions
E e l and Wagne [17] e iew ha AP-1 is a dime ic ansc ip ion ac o ha con ains
membe s om he JUN, FOS, ATF and MAF p o ein amilies. Fu he , wo compo-
nen s o AP-1 i.e, c-JUN and c-FOS, we e i s iden i ied as i al oncop o eins, so
hei ole in umo igenesis is well es ablished. Placen a ion es ablishes he ma e nal-
e al in e ace and is equi ed o success ul p egnancy. The epi helial componen o
6
RANKING @ iUSING HSIC - LINEAR
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
FOSL1-FRAT1-FRZB 17 35368 17731 25382 51767 FOSL1-FRAT1-SENP2 24 25444 38488 23401 24549
CSNK1D-FGF4-FOSL1 30 6054 51426 42593 32863 CXXC4-FOSL1-SENP2 88 36639 18548 29008 12844
CCND1-FGF4-FOSL1 171 44847 19116 31051 26950 CTBP2-CTNNB1-FOSL1 193 49920 22884 20817 52920
CXXC4-FOSL1-PPP2R1A 255 24314 35136 31526 39110 FOSL1-PPP2R1A-SENP2 256 39545 1842 16944 18375
FOSL1-PORCN-SFRP4 292 44876 11834 15903 36394 DKK1-FOSL1-SENP2 326 21740 41468 36036 47108
FOSL1-PORCN-SENP2 349 31659 11861 10245 21849 FOSL1-NLK-SENP2 359 18070 3202 3757 21594
FOSL1-FRAT1-WNT4 372 34237 49971 11736 48629 FOSL1-NLK-WNT4 378 3397 2566 2260 40025
FOSL1-FOXN1-FRZB 426 18495 3914 3925 50337 DKK1-FGF4-FOSL1 432 8047 21605 31028 45972
FOSL1-PORCN-WNT4 455 37570 20729 10105 38487 FOSL1-JUN-SENP2 458 25557 50663 10786 1378
FBXW11-FGF4-FOSL1 485 34731 55734 37270 13666 APC-BCL9-FOSL1 503 44276 12767 10482 56943
CSNK1D-FOSL1-FZD1 568 999 47773 10250 51091 DVL2-FGF4-FOSL1 664 42437 30359 29718 55333
FOSL1-PORCN-WNT2B 670 19667 46545 40946 19709 FOSL1-FRAT1-TLE2 675 26389 36474 6816 48298
FOSL1-FOXN1-SFRP4 680 23049 4982 9425 19314 FOSL1-WIF1-WNT2B 727 2770 23114 37617 17980
CXXC4-FOSL1-FRAT1 731 20058 29538 14504 27891 FOSL1-FOXN1-KREMEN1 742 14009 6113 8523 21187
DAAM1-FGF4-FOSL1 749 45182 54951 56379 34801 DKK1-DVL2-FOSL1 754 5173 30314 36187 56024
FOSL1-SFRP1-WNT2B 802 20624 39428 24273 52148 FOSL1-FOXN1-SENP2 808 25273 3965 4409 8541
FOSL1-FRAT1-FBXW4 832 28714 21515 30364 38569 FOSL1-PPP2R1A-RHOU 846 41555 5035 55239 46031
FOSL1-NKD1-SFRP4 875 160 5276 11851 11033 FZD5-DVL2-FOSL1 982 7285 6435 17317 49867
FOSL1-FOXN1-GSK3B 983 14647 1776 17080 41173 FOSL1-JUN-TCF7 996 16387 31797 50574 23742
FOSL1-JUN-TCF7L1 1000 17132 38816 29827 1621 FOSL1-FZD2-SFRP4 1024 10811 26104 3869 54533
CSNK1G1-DVL2-FOSL1 1061 14048 12622 34641 48959 FOSL1-FOXN1-PPP2CA 1072 22257 16994 9632 25457
CSNK1G1-CXXC4-FOSL1 1094 46700 26853 25310 54546 FOSL1-FZD7-PPP2CA 1103 37962 25642 24479 50931
FOSL1-FRAT1-TCF7L1 1246 18255 19691 45038 20105 FOSL1-FOXN1-SLC9A3R1 1275 28011 885 4881 51370
FOSL1-FOXN1-FZD8 1314 19509 2343 16192 19984 FOSL1-GSK3A-SENP2 1322 23410 370 29385 29247
CSNK2A1-CTNNB1-FOSL1 1324 32995 31993 33693 996 FOSL1-PORCN-RHOU 1333 44749 10281 23020 23848
CXXC4-FGF4-FOSL1 1368 22243 14796 45725 54959 FOSL1-WNT1-WNT2B 1381 1526 2254 11678 47870
FOSL1-FOXN1-LRP5 1396 12463 8896 42948 43152 DVL1-FBXW11-FOSL1 1398 33771 7304 14350 55345
APC-FGF4-FOSL1 1403 38742 14424 52151 37505 FOSL1-NLK-WNT2B 1425 3331 440 49507 31594
FOSL1-GSK3A-SFRP4 1436 32274 8539 22527 42270 FOSL1-PORCN-TLE2 1446 44769 21226 13796 30066
CTBP1-FGF4-FOSL1 1455 29082 37073 39831 41035 FOSL1-JUN-PITX2 1479 1306 37107 54515 12375
FOSL1-FOXN1-TLE2 1506 19146 2341 7352 15489 FOSL1-NLK-WNT3A 1512 2335 4160 3374 12963
AES-EP300-FOSL1 1521 46072 48935 20712 49058 FOSL1-JUN-WNT3A 1542 4890 20754 29478 5342
CSNK2A1-CTBP1-FOSL1 1581 35982 53710 47786 1954 FOSL1-FRAT1-LRP5 1606 10313 45532 19498 50080
EP300-FGF4-FOSL1 1656 55025 38932 40354 51107 FOSL1-FOXN1-RHOU 1660 21880 3384 19296 29104
BCL9-FGF4-FOSL1 1679 19298 42532 40993 55112 FOSL1-GSK3A-GSK3B 1690 15629 2644 46105 37164
FOSL1-JUN-SLC9A3R1 1708 28629 15238 40456 52065 FZD5-FGF4-FOSL1 1718 8030 21299 33264 34465
FZD5-CCND3-FOSL1 1721 5130 11993 34398 15331 FOSL1-PORCN-SFRP1 1757 36317 8057 17969 48972
FOSL1-GSK3A-LRP5 1793 5589 2949 32274 52490 CXXC4-FOSL1-WNT5A 1800 15338 42242 52718 32578
FOSL1-JUN-FBXW4 1801 30399 19599 18597 6617 DIXDC1-FGF4-FOSL1 1834 22981 29680 27665 50757
FGF4-FOSL1-FRAT1 1842 39537 26432 55090 52175 FOSL1-NKD1-PPP2CA 1845 14335 40783 24581 23211
FOSL1-NLK-SFRP1 1846 2471 1853 521 54004 FOSL1-PORCN-FBXW4 1896 35711 18446 8569 19117
FOSL1-PORCN-PPP2CA 1917 33808 39279 26918 22451 CSNK1G1-FGF4-FOSL1 1936 28205 33826 36195 48093
FOSL1-PPP2R1A-SFRP4 1952 52448 1955 16120 30096 FOSL1-FOXN1-WNT5A 2034 6923 6744 9847 23516
FOSL1-FOXN1-TCF7L1 2041 16265 2181 10149 12942 CSNK1D-FOSL1-SENP2 2088 21782 40398 32697 32527
FOSL1-FOXN1-WNT2B 2092 14363 2122 5400 9642 FZD5-CCND2-FOSL1 2169 34455 22205 26665 51389
APC-CCND3-FOSL1 2190 27032 11642 22161 35558 CSNK1A1-FGF4-FOSL1 2196 29619 53247 49107 51945
DKK1-FOSL1-FRAT1 2248 20750 40597 26220 53540 FOSL1-FOXN1-FZD6 2256 14824 19723 8486 53548
FOSL1-PORCN-TCF7L1 2280 27789 13184 15773 14755 DVL1-FGF4-FOSL1 2292 40318 18510 24845 19218
FOSL1-PYGO1-WNT2 2296 35937 10116 9410 31529 FOSL1-MYC-SFRP4 2339 42470 6026 33033 29120
FOSL1-GSK3A-PPP2CA 2355 22861 911 45587 39936 FOSL1-FZD2-GSK3B 2382 12778 19494 45692 50453
FOSL1-FOXN1-FZD1 2391 9360 6982 9851 31253 FOSL1-FZD7-WNT2B 2454 17850 39272 36856 49039
FOSL1-NKD1-SENP2 2466 6869 5781 10026 30259 FOSL1-FOXN1-TCF7 2473 12271 1932 11488 24676
FOSL1-PORCN-SLC9A3R1 2483 39419 13608 18592 31025 FOSL1-WNT1-WNT3A 2512 4481 499 34674 10423
FOSL1-FBXW4-WNT3A 2570 6332 206 39656 6459 FOSL1-WNT1-WNT4 2598 5807 2371 11336 21308
FOSL1-PORCN-TCF7 2655 29633 37738 24610 27978 FOSL1-JUN-PPP2R1A 2696 46872 41797 35276 27908
FOSL1-FOXN1-LRP6 2703 18423 9454 15846 43299 FOSL1-SFRP1-TCF7 2828 29087 33743 34368 53991
CSNK1A1-CTBP2-FOSL1 2849 847 23417 33270 57047 FOSL1-FOXN1-WNT4 2926 19268 4984 7030 42733
DKK1-FOSL1-FRZB 2954 10112 50811 45748 42692 FGF4-FOSL1-SFRP4 2957 29593 15781 53739 51686
FOSL1-GSK3A-KREMEN1 3017 11044 1525 53908 3915 FOSL1-FOXN1-MYC 3046 33641 23663 11459 46671
FOSL1-WNT1-WNT2 3080 12766 6760 15272 13494 FOSL1-FRAT1-FZD7 3142 34552 21454 20799 55831
FOSL1-FOXN1-FBXW4 3153 30885 23159 9810 3473 FGF4-FOSL1-PPP2CA 3175 29507 37541 48577 51007
FOSL1-GSK3A-PITX2 3246 8961 918 7353 12922 FOSL1-FOXN1-WNT2 3267 27111 6567 10866 26206
FGF4-FOSL1-FZD1 3290 40378 18437 35554 52267 FOSL1-JUN-PPP2CA 3303 25232 24882 2685 4764
Table 1: Rankings o FOSL1-X-X. A lis o app oxima ely i s 125 combina ions wi h ankings below
10,000 ou o 57,155. SA - HSIC; Ke nel - linea
he placen a consis s o ophoblas cells, which possess he capaci y o mul ilin-
eage di e en ia ion and a e esponsible o placen a-speci ic unc ions. FOSL1 con-
ibu es o he egula ion o placen al de elopmen . Kubo a e al. [18] showed h ough
7
RANKING @ iUSING HSIC - RBF
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
FOSL1-FRAT1-FRZB 18486 33706 51536 16007 42608 FOSL1-FRAT1-SENP2 15910 20828 47008 39310 20122
CSNK1D-FGF4-FOSL1 3694 6645 6799 4138 45840 CXXC4-FOSL1-SENP2 27232 42351 44650 16863 48178
CCND1-FGF4-FOSL1 19400 39101 15057 5353 6829 CTBP2-CTNNB1-FOSL1 22087 47806 43102 26570 12950
CXXC4-FOSL1-PPP2R1A 52227 34156 6226 46113 43359 FOSL1-PPP2R1A-SENP2 36531 47500 56688 1297 8711
FOSL1-PORCN-SFRP4 1126 41952 37755 38422 51768 DKK1-FOSL1-SENP2 14095 26375 3333 23119 42212
FOSL1-PORCN-SENP2 314 29835 38646 3075 34319 FOSL1-NLK-SENP2 41514 24088 54636 21014 19349
FOSL1-FRAT1-WNT4 29015 37923 40684 6763 23547 FOSL1-NLK-WNT4 46914 7268 50547 1274 44200
FOSL1-FOXN1-FRZB 1736 15846 50466 9743 17620 DKK1-FGF4-FOSL1 4252 18471 3345 22302 52225
FOSL1-PORCN-WNT4 4252 18471 3345 22302 52225 FOSL1-JUN-SENP2 15271 29847 41615 22047 48378
FBXW11-FGF4-FOSL1 9717 17062 12881 5316 18991 APC-BCL9-FOSL1 26374 51523 20691 9548 17725
CSNK1D-FOSL1-FZD1 14359 1015 37515 5753 14234 DVL2-FGF4-FOSL1 3167 48007 8628 17742 42623
FOSL1-PORCN-WNT2B 4296 5489 1279 29512 55035 FOSL1-FRAT1-TLE2 33776 19243 42932 10498 52900
FOSL1-FOXN1-SFRP4 3581 13413 50450 24051 14731 FOSL1-WIF1-WNT2B 41773 13018 2276 54404 49689
CXXC4-FOSL1-FRAT1 46607 15174 26086 25252 40912 FOSL1-FOXN1-KREMEN1 2901 4767 41791 45598 13163
DAAM1-FGF4-FOSL1 2515 51205 7449 23613 7495 DKK1-DVL2-FOSL1 32822 15198 12108 3507 28223
FOSL1-SFRP1-WNT2B 21116 7705 2123 56839 56883 FOSL1-FOXN1-SENP2 1644 24800 52856 5786 32696
FOSL1-FRAT1-FBXW4 36692 36234 15133 298 43524 FOSL1-PPP2R1A-RHOU 19254 49825 54278 50968 41085
FOSL1-NKD1-SFRP4 38557 1693 50390 24818 21820 FZD5-DVL2-FOSL1 31108 15865 56297 1825 46027
FOSL1-FOXN1-GSK3B 31108 15865 56297 1825 46027 FOSL1-JUN-TCF7 31108 15865 56297 1825 46027
FOSL1-JUN-TCF7L1 5134 9823 24616 52464 27691 FOSL1-FZD2-SFRP4 4647 1210 36429 2252 17735
CSNK1G1-DVL2-FOSL1 24608 32567 25022 2699 31491 FOSL1-FOXN1-PPP2CA 2050 20570 56654 7068 31115
CSNK1G1-CXXC4-FOSL1 18872 46435 17556 11771 54033 FOSL1-FZD7-PPP2CA 54451 46826 3194 28518 28447
FOSL1-FRAT1-TCF7L1 6305 18815 46524 19747 38837 FOSL1-FOXN1-SLC9A3R1 3153 36795 52930 36241 48302
FOSL1-FOXN1-FZD8 2757 28761 55000 20964 54956 FOSL1-GSK3A-SENP2 3309 21823 56135 50608 24479
CSNK2A1-CTNNB1-FOSL1 26592 26504 31836 43474 14209 FOSL1-PORCN-RHOU 1550 39845 36998 42942 56120
CXXC4-FGF4-FOSL1 553 41867 29836 8057 53097 FOSL1-WNT1-WNT2B 8040 5830 31727 31 46871
FOSL1-FOXN1-LRP5 6494 8694 40579 24357 5973 DVL1-FBXW11-FOSL1 19045 18319 56904 35 28285
APC-FGF4-FOSL1 11913 34261 19328 3356 53756 FOSL1-NLK-WNT2B 20492 705 35136 30860 53018
FOSL1-GSK3A-SFRP4 6589 36249 56048 37361 34223 FOSL1-PORCN-TLE2 11375 42064 44489 3406 53873
CTBP1-FGF4-FOSL1 4851 14275 24640 778 55018 FOSL1-JUN-PITX2 42099 14135 52254 57017 24935
FOSL1-FOXN1-TLE2 2685 18230 45559 25782 35344 FOSL1-NLK-WNT3A 51755 5242 44005 49978 52983
AES-EP300-FOSL1 43507 49548 17732 5048 38399 FOSL1-JUN-WNT3A 37744 27522 48171 53533 24924
CSNK2A1-CTBP1-FOSL1 48595 20470 4367 24006 8607 FOSL1-FRAT1-LRP5 50831 2200 13168 50933 31960
EP300-FGF4-FOSL1 4014 52588 15864 2361 53651 FOSL1-FOXN1-RHOU 1989 10797 48585 37026 31459
BCL9-FGF4-FOSL1 17209 16838 16284 7375 47320 FOSL1-GSK3A-GSK3B 1419 30732 55587 54721 53577
FOSL1-JUN-SLC9A3R1 39137 42805 45435 35330 23074 FZD5-FGF4-FOSL1 3050 25364 36566 13304 54934
FZD5-CCND3-FOSL1 38034 34654 56227 16297 18221 FOSL1-PORCN-SFRP1 10522 38362 29766 6077 55724
FOSL1-GSK3A-LRP5 14584 286 49671 55368 36879 CXXC4-FOSL1-WNT5A 53822 4385 5771 55698 30961
FOSL1-JUN-FBXW4 28709 31696 9585 5972 36656 DIXDC1-FGF4-FOSL1 2494 21424 29421 5565 13873
FGF4-FOSL1-FRAT1 36045 19108 7369 17738 6729 FOSL1-NKD1-PPP2CA 21934 29546 42661 35675 17456
FOSL1-NLK-SFRP1 34233 941 55096 25592 35663 FOSL1-PORCN-FBXW4 996 45964 6696 11811 50330
FOSL1-PORCN-PPP2CA 857 51996 6161 7188 48966 CSNK1G1-FGF4-FOSL1 30497 29781 8021 11753 43558
FOSL1-PPP2R1A-SFRP4 50064 57024 56666 31648 53883 FOSL1-FOXN1-WNT5A 5307 14590 45152 44826 55367
FOSL1-FOXN1-TCF7L1 502 20490 56294 30140 13635 CSNK1D-FOSL1-SENP2 20750 28948 9391 39658 39465
FOSL1-FOXN1-WNT2B 3731 11944 46580 2296 53387 FZD5-CCND2-FOSL1 3513 41975 54460 12813 30675
APC-CCND3-FOSL1 43650 23498 55526 7318 50103 CSNK1A1-FGF4-FOSL1 16622 30625 6828 2304 55529
DKK1-FOSL1-FRAT1 33541 20184 16489 26495 35744 FOSL1-FOXN1-FZD6 4046 6143 29686 14520 37535
FOSL1-PORCN-TCF7L1 731 8052 33790 38315 51524 DVL1-FGF4-FOSL1 17015 27364 12609 5371 33295
FOSL1-PYGO1-WNT2 4646 17601 54904 1115 45855 FOSL1-MYC-SFRP4 2575 51076 50017 35470 8587
FOSL1-GSK3A-PPP2CA 12185 33599 52257 41997 37270 FOSL1-FZD2-GSK3B 5098 22623 40747 48566 47602
FOSL1-FOXN1-FZD1 1950 8922 42094 2898 13807 FOSL1-FZD7-WNT2B 50187 4425 4093 55495 52155
FOSL1-NKD1-SENP2 15372 3697 55084 25337 9352 FOSL1-FOXN1-TCF7 1675 7202 46849 34237 39333
FOSL1-PORCN-SLC9A3R1 7522 46541 51243 1546 46102 FOSL1-WNT1-WNT3A 9692 5532 35479 30879 13078
FOSL1-FBXW4-WNT3A 40808 8862 52958 56668 7351 FOSL1-WNT1-WNT4 4799 4228 46889 440 32783
FOSL1-PORCN-TCF7 851 19236 7477 4033 41750 FOSL1-JUN-PPP2R1A 20816 55928 16147 47523 47242
FOSL1-FOXN1-LRP6 8216 12122 52031 24335 23358 FOSL1-SFRP1-TCF7 6118 26200 9358 53523 34103
CSNK1A1-CTBP2-FOSL1 34000 288 23729 11736 43862 FOSL1-FOXN1-WNT4 2275 8743 50316 14275 47768
DKK1-FOSL1-FRZB 15443 4827 12607 32034 48635 FGF4-FOSL1-SFRP4 34496 9590 20805 42045 6769
FOSL1-GSK3A-KREMEN1 5655 3612 51883 54394 46466 FOSL1-FOXN1-MYC 7089 25106 47390 44956 48333
FOSL1-WNT1-WNT2 7001 10490 53012 815 33966 FOSL1-FRAT1-FZD7 7001 10490 53012 815 33966
FOSL1-FOXN1-FBXW4 3141 36195 30061 7895 5125 FGF4-FOSL1-PPP2CA 42277 28170 8091 25442 19223
FOSL1-GSK3A-PITX2 22118 26574 53921 57069 41599 FOSL1-FOXN1-WNT2 4844 21073 49643 390 10186
FGF4-FOSL1-FZD1 39663 26051 18681 32329 5201 FOSL1-JUN-PPP2CA 21063 49029 6511 48244 44672
Table 2: Rankings o FOSL1-X-X. A lis o app oxima ely i s 125 combina ions wi h ankings below
10,000 ou o 57,155. SA - HSIC; Ke nel - b
co-immunop ecipi a ion, co-immunolocaliza ion, and ChIP analyses, ha FOSL1 in-
e ac ed wi h JUNB and, o a lesse ex en , JUN in di e en ia ing ophoblas cells.
Knockdown o FOSL1 and JUNB exp ession inhibi ed bo h endoc ine and in asi e
p ope ies o ophoblas cells. Looking a he ables abo e, one inds he ollowing
8
RANKING @ iUSING SOBOL - 2002
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
FOSL1-FRAT1-FRZB 48750 46940 49058 47805 7521 FOSL1-FRAT1-SENP2 11214 7586 5074 7384 41915
CSNK1D-FGF4-FOSL1 31433 17351 34702 49796 3779 CXXC4-FOSL1-SENP2 9857 21302 3091 25681 49127
CCND1-FGF4-FOSL1 47946 1732 38933 38678 23755 CTBP2-CTNNB1-FOSL1 12477 34215 13015 7117 42120
CXXC4-FOSL1-PPP2R1A 33024 20784 45045 33319 8066 FOSL1-PPP2R1A-SENP2 17310 2495 82 9104 48865
FOSL1-PORCN-SFRP4 44543 52571 34231 46029 13871 DKK1-FOSL1-SENP2 3431 3346 23554 20246 9046
FOSL1-PORCN-SENP2 54760 25670 47342 32899 26575 FOSL1-NLK-SENP2 13461 35727 546 20026 44857
FOSL1-FRAT1-WNT4 11661 37114 3277 931 53168 FOSL1-NLK-WNT4 11701 13725 13502 3308 41595
FOSL1-FOXN1-FRZB 4845 4217 9346 8710 50240 DKK1-FGF4-FOSL1 56316 11460 37809 55590 6360
FOSL1-PORCN-WNT4 47380 31804 36756 47696 19151 FOSL1-JUN-SENP2 51877 55400 52885 34018 3734
FBXW11-FGF4-FOSL1 32715 28640 35906 29158 11589 APC-BCL9-FOSL1 15337 18912 25043 17653 30357
CSNK1D-FOSL1-FZD1 33939 40307 29863 45255 32407 DVL2-FGF4-FOSL1 28814 41386 42144 48902 4193
FOSL1-PORCN-WNT2B 9686 2290 2189 14059 39340 FOSL1-FRAT1-TLE2 50038 6818 42415 47626 4928
FOSL1-FOXN1-SFRP4 45107 48753 50599 52560 3992 FOSL1-WIF1-WNT2B 25173 2114 24567 1335 44580
CXXC4-FOSL1-FRAT1 13778 2749 16108 6403 43145 FOSL1-FOXN1-KREMEN1 5566 2122 4725 4323 49299
DAAM1-FGF4-FOSL1 39718 54241 55152 47140 6015 DKK1-DVL2-FOSL1 53868 6384 55605 30940 12601
FOSL1-SFRP1-WNT2B 36889 18888 44464 53547 13962 FOSL1-FOXN1-SENP2 50427 48059 30743 46224 6709
FOSL1-FRAT1-FBXW4 37417 42346 33119 29950 927 FOSL1-PPP2R1A-RHOU 40904 5712 55181 51304 16176
FOSL1-NKD1-SFRP4 26523 39016 6871 18225 44405 FZD5-DVL2-FOSL1 40182 25866 35056 29369 7043
FOSL1-FOXN1-GSK3B 284 8167 4904 8619 50083 FOSL1-JUN-TCF7 49067 35754 42264 40921 9123
FOSL1-JUN-TCF7L1 4213 41297 24152 15364 47738 FOSL1-FZD2-SFRP4 25818 32267 25224 27273 48695
CSNK1G1-DVL2-FOSL1 13304 16111 11364 20166 55668 FOSL1-FOXN1-PPP2CA 51329 15073 48971 51617 23899
CSNK1G1-CXXC4-FOSL1 25168 1437 11571 16056 25721 FOSL1-FZD7-PPP2CA 35591 32520 50960 44000 21144
FOSL1-FRAT1-TCF7L1 50590 19180 53417 52474 6976 FOSL1-FOXN1-SLC9A3R1 34742 13119 54271 41553 7238
FOSL1-FOXN1-FZD8 18145 45592 11421 12903 51267 FOSL1-GSK3A-SENP2 11356 7709 5408 9588 41158
CSNK2A1-CTNNB1-FOSL1 7348 26679 6679 8520 40678 FOSL1-PORCN-RHOU 2397 31652 9884 24315 30810
CXXC4-FGF4-FOSL1 52810 50470 34544 37927 3516 FOSL1-WNT1-WNT2B 27112 14023 16313 6628 52241
FOSL1-FOXN1-LRP5 19194 9612 13710 10552 49252 DVL1-FBXW11-FOSL1 1086 49040 10558 27196 54543
APC-FGF4-FOSL1 39629 40499 37919 40405 7494 FOSL1-NLK-WNT2B 42013 9877 52887 52662 11462
FOSL1-GSK3A-SFRP4 24080 48870 2981 6458 47742 FOSL1-PORCN-TLE2 11344 44887 618 8380 48021
CTBP1-FGF4-FOSL1 30113 26329 54976 56153 8704 FOSL1-JUN-PITX2 29544 47341 44123 52018 7644
FOSL1-FOXN1-TLE2 10111 34166 2997 1459 46410 FOSL1-NLK-WNT3A 43309 33771 50006 38500 4467
AES-EP300-FOSL1 27689 20431 21551 25851 56678 FOSL1-JUN-WNT3A 10579 5753 10670 19639 21636
CSNK2A1-CTBP1-FOSL1 51466 6276 44543 34556 2632 FOSL1-FRAT1-LRP5 31351 10581 42739 34529 664
EP300-FGF4-FOSL1 28028 36636 4319 2494 42274 FOSL1-FOXN1-RHOU 6665 9152 26476 10977 50432
BCL9-FGF4-FOSL1 101 1534 21498 16607 27262 FOSL1-GSK3A-GSK3B 53394 55855 50166 49917 857
FOSL1-JUN-SLC9A3R1 43183 49105 41385 39275 5077 FZD5-FGF4-FOSL1 46553 12322 55789 43921 10970
FZD5-CCND3-FOSL1 4245 7266 11704 15340 18858 FOSL1-PORCN-SFRP1 12651 4591 23008 11171 43358
FOSL1-GSK3A-LRP5 41882 45860 41982 56323 1496 CXXC4-FOSL1-WNT5A 45823 54747 52368 41434 48001
FOSL1-JUN-FBXW4 13997 8027 15717 17898 52096 DIXDC1-FGF4-FOSL1 3396 43706 23582 7101 52388
FGF4-FOSL1-FRAT1 10083 6588 8685 24287 30035 FOSL1-NKD1-PPP2CA 2142 38096 5085 20731 35691
FOSL1-NLK-SFRP1 43758 21393 56612 37171 12178 FOSL1-PORCN-FBXW4 19295 6262 4610 7514 13534
FOSL1-PORCN-PPP2CA 48261 18485 32801 52162 23392 CSNK1G1-FGF4-FOSL1 8963 28835 12476 27024 48361
FOSL1-PPP2R1A-SFRP4 11157 1063 12252 1915 27364 FOSL1-FOXN1-WNT5A 8341 10381 8155 9375 49603
FOSL1-FOXN1-TCF7L1 6256 50998 4857 10230 51120 CSNK1D-FOSL1-SENP2 27384 17302 26341 7301 43654
FOSL1-FOXN1-WNT2B 1186 35009 15480 12827 50006 FZD5-CCND2-FOSL1 13152 46996 20245 4220 49402
APC-CCND3-FOSL1 14004 19135 18446 27673 7344 CSNK1A1-FGF4-FOSL1 31936 30526 31908 35528 15251
DKK1-FOSL1-FRAT1 3553 54257 16310 25765 12367 FOSL1-FOXN1-FZD6 13640 15481 10464 19959 46450
FOSL1-PORCN-TCF7L1 14669 55 993 18720 27063 DVL1-FGF4-FOSL1 45386 4232 46196 56492 27411
FOSL1-PYGO1-WNT2 47297 50999 30260 50806 4015 FOSL1-MYC-SFRP4 48771 44097 44821 42504 15359
FOSL1-GSK3A-PPP2CA 1409 42580 3372 20682 38693 FOSL1-FZD2-GSK3B 30096 21061 34538 29703 9399
FOSL1-FOXN1-FZD1 25925 10874 2904 9032 52484 FOSL1-FZD7-WNT2B 21619 45 3513 13198 43493
FOSL1-NKD1-SENP2 16870 1004 11411 25457 43247 FOSL1-FOXN1-TCF7 49708 52975 52794 35953 2727
FOSL1-PORCN-SLC9A3R1 37873 50909 52614 49669 43825 FOSL1-WNT1-WNT3A 15630 39992 11099 5546 48850
FOSL1-FBXW4-WNT3A 14577 48454 4103 4489 48405 FOSL1-WNT1-WNT4 41560 17077 46101 51615 8307
FOSL1-PORCN-TCF7 30681 31215 55178 44882 16830 FOSL1-JUN-PPP2R1A 21985 646 17395 14514 28922
FOSL1-FOXN1-LRP6 37870 47647 43468 46668 7859 FOSL1-SFRP1-TCF7 2040 20827 11649 18240 45367
CSNK1A1-CTBP2-FOSL1 43122 17498 29136 41748 25756 FOSL1-FOXN1-WNT4 53448 12 54578 41681 9465
DKK1-FOSL1-FRZB 53609 2816 40791 31392 44680 FGF4-FOSL1-SFRP4 20560 6324 9945 23630 45285
FOSL1-GSK3A-KREMEN1 52307 56531 47402 55645 3684 FOSL1-FOXN1-MYC 10915 26427 7515 6321 53618
FOSL1-WNT1-WNT2 34611 47563 33805 56132 5656 FOSL1-FRAT1-FZD7 4534 8444 3333 12890 53657
FOSL1-FOXN1-FBXW4 22313 44309 2923 15637 49928 FGF4-FOSL1-PPP2CA 2668 4065 11722 25274 53689
FOSL1-GSK3A-PITX2 3336 36071 6692 8964 29002 FOSL1-FOXN1-WNT2 47191 48365 52960 44342 6468
FGF4-FOSL1-FZD1 32182 13714 52916 30292 9916 FOSL1-JUN-PPP2CA 47425 55951 39423 37994 17117
Table 3: Rankings o FOSL1-X-X. A lis o app oxima ely i s 125 combina ions wi h ankings below
10,000 ou o 57,155. SA - SOBOL; Implemen a ion - 2002
combina ions o JUN along wi h FOSL1, o be p ominen a 3 d o de le el - FOSL1-
JUN-TCF7L1, FOSL1-JUN-SLC9A3R1, FOSL1-JUN-FBXW4, FOSL1-JUN-SENP2,
FOSL1-JUN-TCF7, FOSL1-JUN-PITX2, FOSL1-JUN-WNT3A, FOSL1-JUN-PPP2R1A
and FOSL1-JUN-PPP2CA. All hese combina ions indica e he exis ence o a possible
9
[14] A. Sal elli, Making bes use o model e alua ions o compu e sensi i i y indices, Compu e physics communica ions
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