Deregulation of the non-coding genome in leukemia

Full Te ms & Condi ions o access and use can be ound a h p://www. and online.com/ac ion/jou nalIn o ma ion?jou nalCode=k nb20 Download by: [Tampe e Uni e si y] Da e: 17 Augus 2017, A : 00:31 RNA Biology ISSN: 1547-6286 (P in ) 1555-8584 (Online) Jou nal homepage: h p://www. and online.com/loi/k nb20 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. Submi you a icle o his jou nal A icle iews: 277 View ela ed a icles View C ossma k da a 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 Downloaded by [Tampe e Uni e si y] a 00:31 17 Augus 2017 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. Downloaded by [Tampe e Uni e si y] a 00:31 17 Augus 2017 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 Re e ences 1. ENCODE P ojec Conso ium TEP, Bi ney E, S ama oyannopoulos JA, Du a A, Guig oR,Ginge asTR, Ma gulies EH, Weng Z, Snyde M, De mi zakis ET, e al. Iden ifi- ca ion and analysis o unc ional elemen s in 1% o he human genome by he ENCODE pilo p ojec . Na u e 2007; 447:799-816; PMID:17571346; h ps://doi.o g/10.1038/na u e05874 2. ENCODE P ojec Conso ium TEP, Be ns ein BE, Bi ney E, Dunham I, G een ED, Gun e C, Snyde M. An in eg a ed encyclopedia o DNA elemen s in he human genome. 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