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RNA Biology
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De egula ion o he non-coding genome in
leukemia
Susanna Teppo , Me ja Heinäniemi & Olli Lohi
To ci e his a icle: Susanna Teppo , Me ja Heinäniemi & Olli Lohi (2017) De egula ion o he non-
coding genome in leukemia, RNA Biology, 14:7, 827-830, DOI: 10.1080/15476286.2017.1312228
To link o his a icle: h p://dx.doi.o g/10.1080/15476286.2017.1312228
© 2017 The Au ho (s). Published wi h
license by Taylo & F ancis G oup, LLC©
Susanna Teppo, Me ja Heinäniemi, and Olli
Lohi
Accep ed au ho e sion pos ed online: 07
Ap 2017.
Published online: 07 Ap 2017.
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POINT OF VIEW
De egula ion o he non-coding genome in leukemia
Susanna Teppo
a
, Me ja Hein€
aniemi
b
, and Olli Lohi
a
a
Tampe e Cen e o Child Heal h Resea ch, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e and Tampe e Uni e si y Hospi al, Tampe e,
Finland;
b
Ins i u e o Biomedicine, School o Medicine, Uni e si y o Eas e n Finland, Kuopio, Finland
ARTICLE HISTORY
Recei ed 7 Feb ua y 2017
Re ised 21 Ma ch 2017
Accep ed 24 Ma ch 2017
ABSTRACT
Me hodological ad ances ha allow deepe cha ac e iza ion o non-coding elemen s in he genome ha e
s a ed o e eal he ull spec um o de egula ion in cance . We gene a ed an inducible cell model o
ack ansc ip ional changes a e induc ion o a well-known leukemia-inducing usion gene, ETV6-RUNX1.
Ou da a e ealed widesp ead ansc ip ional al e a ions ou side coding elemen s in he genome. This
adds o he g owing lis o a ious al e a ions in he non-coding genome in cance and pinpoin s hei ole
in diseased cellula s a e.
KEYWORDS
eRNA; GRO-seq; leukemia;
nascen RNA; ansc ip ional
egula ion
App oxima ely 80 % o he genome is ansc ibed in o RNA
species in a leas some cell ype o a some s age o de elop-
men .
1,2
Non-coding egula o y (non-housekeeping) RNAs a e
cu en ly defined by hei size, genomic loca ion o p esump-
i e unc ion. Enhance RNAs (eRNA), which ha e a leng h
span om 0.1 o 10 kb, mainly all in o he ca ego y o long
non-coding RNAs (lncRNAs) al hough hey a e be e defined
by hei ansc ip ional egula o y unc ion. La ge clus e s o
enhance s wi h mul iple ansc ip ion ac o (TF) binding si es
and open ch oma in ma ks a e e med supe -enhance s and
hey define cell iden i y.
3,4
Loca ions o enhance elemen s a e
o en deduced om ce ain his one ma ks (H3K4me1,
H3K27ac), ansc ip ion ac o binding p ofiles (p300), o open
ch oma in s a es (eg. DNAse- and ATAC-seq). The de elop-
men o global nascen RNA sequencing echniques, such as
global un-on sequencing (GRO-seq),
5
has e ealed ha an-
sc ip ion o eRNAs is highly co ela ed wi h ma ks such as
H3K27ac ( o e iew see e . 6) and o ansc ip ion a nea by
gene p omo e s,
7,8
and is conside ed he mos eliable ma k o
an ac i e enhance .
7,9
The unc ions o eRNAs a e ye unclea :
hey can be passi e byp oduc s o ansc ip ion o unc ion
ac i ely in ec ui men o ansc ip ion ac o s ( e iewed in
e . 10), like in he case o Yin-Yang (YY)1.
11
Mis egula ion o ncRNAs is common in cance al hough
ecu en s uc u al a ia ions ha e been challenging o find.
Fo example, in a s udy wi h whole-genome sequencing o 150
umo /no mal pai s o ch onic lymphocy ic leukemia, only one
ecu en non-coding mu a ion clus e was ound a a po en ial
egula o y elemen .
12
Howe e , his may also eflec he lacking
anno a ions. We ecen ly analyzed whole genome sequencing
da a om p ecu so B-cell acu e lymphoblas ic leukemia
(p e-B-ALL) in he con ex o ch oma in a chi ec u e and
ound ha he opologically associa ed domains wi h he
highes numbe o b eakpoin s con ained unanno a ed
ncRNAs.
13
Func ional s udies manipula ing lncRNA p oduc-
ion in leukemia ha e shown di e se oles in cance - ela ed
pa hways.
14-16
In addi ion, unc ional s udies on enhance s
ha e highligh ed hei o e all ole in cance , as e iewed in
e . 17. In leukemia, soma ic mu a ion o a non-coding elemen
gene a ed a MYB binding si e ups eam o oncogenic TAL1
locus, and a dele ion o he mu a ed (bu no wild ype allele)
supe -enhance in a T-ALL cell line dec eased exp ession o
TAL1 and impai ed cell su i al.
18
Al e ed ansc ip ion a
enhance s may also esul om s uc u al o quan i a i e
changes in bo h enhance elemen s and hei egula ing
p o eins. Duplica ion o NOTCH1-d i en MYC enhance
wasobse edinT-ALLandi s ele ancedemons a edin
a mouse knockou model.
19
Mo eo e , abe a ions in ch o-
ma in s uc u e and especially in insula o egions induce
abno mal gene exp ession, as exemplified by ac i a ion o
TAL1 due o a dele ion o ups eam insula o elemen .
20
Mis egula ed ansc ip ion du ing delica e di e en ia ion
p ocesses in haema opoie ic p ecu so s may also cause
cance by p edisposing o seconda y mu a ions. Con e -
gen ansc ip ion and RNA polyme ase II s alling s ongly
co ela e wi h s uc u al a ia ion clus e s and seem o
p o ide ulne able egions o RAG and AID media ed
double s and b eaks in lymphoma and leukemia.
13,21
Al hough ncRNA exp ession p ofiles using mic oa ay o
RNA-seq ha e been published (eg. e s. 22-26), many
nascen ansc ip s ha e emained unno iced because o
apid deg ada ion o se e al ncRNA species. New me hods
o add ess his challenge ha e eme ged, such as GRO-seq,
PRO-seq o TT-seq ha enable moni o ing a ious
nascen ansc ip s and engaged RNA polyme ase II in
leukemia.
27,28
CONTACT Susanna Teppo susanna. eppo@u a.fiTampe e Cen e o Child Heal h Resea ch, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e,
Laaka inka u 1, A o, Tampe e 33520, Finland.
Published wi h license by Taylo & F ancis G oup, LLC © Susanna Teppo, Me ja Hein€
aniemi, and Olli Lohi
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion-NonComme cial-NoDe i a i es License (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/),
which pe mi s non-comme cial e-use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed, and is no al e ed, ans o med, o buil upon in any way.
RNA BIOLOGY
2017, VOL. 14, NO. 7, 827–830
h ps://doi.o g/10.1080/15476286.2017.1312228
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We add essed his issue in he ETV6-RUNX1 (E/R, TEL-
AML1) usion posi i e leukemia,
30
which ep esen s 25 %
o pedia ic acu e lymphoblas ic leukemias, and causes al e -
a ions in gene exp ession ha p edispose o leukemia.
29
Wi h he help o an inducible E/R cell model and GRO-seq,
we explo ed dynamics o gene exp ession and he ac i i y
o hei egula o y elemen s simul aneously, exposing he
ansc ip ional ci cui y downs eam o he E/R usion
(Fig. 1).
30
We analyzed enhance s based on eRNA
co ela ion wi h GRO-seq signal change a di e en ially
exp essed genes ( ansc ip -cen ic app oach). Secondly, we
gene a ed an enhance -cen ic app oach ha di ec ly
applied he s a is ical amewo k on eRNA le els o iden i y
significan ly egula ed enhance s (enhance anno a ion was
based on H3K27ac and RUNX1 ChIP-seq da a) and co e-
la ed hese changes o ha o nea by ansc ip s. We ound
a leas one simila ly al e ed pu a i e enhance elemen
wi hin C/¡400 kb o almos all he de egula ed coding
ansc ip s using ansc ip -cen ic app oach. E/R egula ed
app oxima ely 20% o ansc ibed egions wi h RUNX1
ChIP peaks, and 5% o CD19/20 (B-cell)- ela ed enhance s.
In e es ingly, CD19/20 specific supe -enhance s we e mos ly
down egula ed, implying a way o E/R o a es cell
di e en ia ion.
I has been p oposed ha any ansc ip ion may possess
egula o y ac i i y. A ecen s udy showed ha hal o he
s udied ansc ibed gene loci (12 lncRNA and 6 mRNA)
egula ed a nea by gene in cis independen ly o whe he he
locus was a coding o non-coding one.
31
As he non-coding
genome is only weakly conse ed,
1,32
mos non-coding
egions may unc ion in a way which is no dependen on
he sequence o ansc ip i sel bu a he he sequence o
i sp omo e o i sloca ionin hegenome.In hecaseo
E/R leukemia, we classified 57 de egula ed no el lncRNAs
(o e 5kblong)asei he po en ialeRNAso lncRNAs
based on he GRO-seq signal. One ou h o he no el and
3 o 7 anno a ed ansc ip s we e conco dan ly di e en ially
exp essed in RNA-seq da a wi h 8 E/R-posi i e and 9 o he
sub ype p e-B-ALL pa ien s.
30
Fo example, KCNQ1OT1,
which ac s in epigene ic egula ion,
33-35
was up egula ed in
ou E/R cell model GRO-seq and he pa ien
RNA-seq da a. Signal changes a ZEB1 and ZEB1-AS1 se e
as an example o a simul aneous down egula ion o gene
and i s p omo e -associa ed RNA, wi h ZEB also being
linked o cance
36,37
and la e B cell di e en ia ion.
38
Func-
ional oles o he no el ansc ip s in E/R leukemia
emains o be explo ed in u u e. Nascen RNA p ofiles o
diagnos ic pa ien samples o dis inc ALL sub ypes will
gi e u he insigh s in o he de ailed ansc ip ional ne -
wo k downs eam o he oncogenic TF usions.
Al eady, housands o egula o y lncRNA ansc ip s
39
and hund eds o housands o enhance egions ha e been
ound. I is now known ha ncRNAs a e widely specific o
a ce ain cell ype and de elopmen al s age. Fo example,
mos lncRNAs ha a e exp essed a a ious s ages o mouse
B cell de elopmen a e no exp essed in a closely ela ed T-
cell lineage.
40
A ecen s udy no ed ha dis al egula o y
elemen s a ied ac oss dis inc haema opoie ic lineages so
ha hey a e be e disc imina o s o cell iden i y han
mRNA le els.
41
This was also eflec ed in ou wo k, whe e
we no iced ha sample sepa a ion based on quan ifica ion
o global eRNA ansc ip ion was equally good as ha based
on quan ifica ion o ansc ip ion a p o ein coding
egions.
30
We can assume ha he inc easing knowledge o
he in e play be ween a ious elemen s o genome and hei
ansc ip ional p oduc s will significan ly con ibu e o ou
unde s anding o he di e se ypes o leukemia and cance
in nea u u e.
Figu e 1. (A) A schema ic ep esen a ion o he ETV6-RUNX1 (E/R, TEL-AML1)
usion p o ein esul ing om a ecu en (12;21) ansloca ion in pedia ic p e-B
acu e lymphoblas ic leukemia. ETV6-RUNX1 includes he poin ed (PNT) domain o
ETS a ian 6 (ETV6) bu lacks he ETS domain ha is in ol ed in DNA binding o
he no mal TF p o ein. The 480 aa long RUNX1 a ian 1 (AML-1c, NP_001745) is
illus a ed wi h he poin mu a ion R201Q in he Run domain which impedes i s
DNA binding capabili y ( his was used o gene a e E/Rmu in e . 30). ID DRunx
inhibi o y domain. (B) GRO-seq signal (nascen RNA ansc ip ion) is shown o E/R-
nega i e as ed and E/R-posi i e samples as blue acks a an example genomic
egion. Signals abo e and below he axis indica e plus and minus s ands, espec-
i ely. RUNX1 ChIP peaks in SEM cells (GSE42075, e . 42) and an enhance ma ke
H3K4me1 ChIP-seq in B-cells (GM12878, e . 2) a e shown and coincide wi h he
GRO-seq signal. Th ee enhance egions ha a e down egula ed by E/R ia
RUNX1-media ed binding a e highligh ed. Nalm6-E/R D24h exp ession o E/R in a
p e-B-ALL cell line; REH DE/R-posi i e cell line; p e-B-ALL o he DE/R-nega i e
pa ien ; p e-B-ALL E/RCDE/R-posi i e pa ien .
828 S. TEPPO ET AL.
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Disclosu e o po en ial conflic s o in e es
No po en ial conflic s o in e es we e disclosed.
ORCID
Susanna Teppo h p://o cid.o g/0000-0003-2569-8030
Me ja Hein€
aniemi h p://o cid.o g/0000-0001-6190-3439
Olli Lohi h p://o cid.o g/0000-0001-9195-0797
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