ICSB2016 187-P-S Conclusion Motivation References [1] arrhythmicity. 1: Figure questions: following the address We E-boxes, ROR-elements(RREs). as and D-boxes, such elements cis-regulatory over loops transcriptional involves rhythms circadian the to adopt to system timing nous This mammals. including large species, a of in fraction rhythms daily controls clock circadian The [2] [3] [5] [4] ,9 n t xetdpaeodrn t with fits ordering [8]. phase data expected expression recent its and 9] 7, [1, the arrhythmicity to includes lead Repressilator knockouts whose the genes that out, turns It of source settings. responsible chosen the the under that rhythms confirmed is model repressilator the this of analyses Further oscillations. sustained for essential most amla-adb 5 ]i ln circadian plant in of 3] context the [5, rhythms. in by [6] and by mammalian- mentioned also was conditions. It untuned evolutionarily under oscillations even generating of [2], capability oscillators its synthetic showing of intro- paradigm a been as already duced has motif the Interestingly, regulations clock core to importances cur- autoregula- and of loops—PER/CRY tion elements debated combines rently repressilator The inhibi- the subsequent of a tion model, data-driven our In edetected? be loops unknown previously Can essential? more REV-ERB or PER/CRY via regulations Are rhythms? sustained generate can loops feedback Which a h ta.Rglto fcrainbhvoradmtbls yREV-ERB by and behaviour circadian of Regulation al. et Cho Han ihe lwt n tnsa ebe.Asnhtcoclaoyntoko rncitoa regulators. transcriptional of network oscillatory synthetic A Leibler. Stanislas and Elowitz B Michael 2012. 123–127, aha o ta.Kre rhtcueo h eei icir fteaaiosscrainsystem. circadian arabidopsis the of circuitry genetic the of architecture Kernel al. et Foo Mathias 2000. 403:335–338, lxnr ohloe l h lc eecruti rbdpi nldsarpesltrwt diinlfeedback additional with repressilator a includes arabidopsis in circuit gene clock loops. The al. et tissues. Pokhilko mammalian Alexandra in genes circadian of Timing Korenˇciˇc al. Anja et 2016. 12:e1004748, Biol, amla icda lc contains Clock Circadian Mammalian :7,2012. 8:574, biology, systems Molecular ncot fRpesltreeet edn to leading elements Repressilator of Knockouts Patrick Pett Modelling Networks andCircuits Rev-erb–Bmal1 4 period 24h a vle hogotevolution throughout evolved has .PtikPt,Aj oeˇicadHnptrHerzel Korenˇciˇc Hanspeter Anja and Pett, Patrick J. nttt o hoeia ilg,H eln UBerlin FU Berlin, HU Biology, Theoretical for Institute fteslrdy Generating day. solar the of Per2, feedback—reassigning Cry1 and Repressilator Rev-erba endoge- is :72 2014. 4:5782, reports, Scientific diinldata Additional regulations essential Extracting B) regulations known of Model A) the → 18 18 17 19 17 19 16 20 16 20 15 21 15 21 skeletal muscle oi ald"ersiao"i h ieaue ihihe ntefiue h ewr otiigol the only containing network alone. The oscillations figure. sustained generate the to in able highlighted still literature, is the Repressilator isolated in "repressilator" called motif a eeteprmna aao eea ise [8] repres- mechanism the silator tissues with consistent several ordering phase of shows data experimental Recent ttrsotthat out turns It h ahmtclmdlwsaaye yexamining by analyzed was model mathematical The α 14 22 14 22 17 n REV-ERB and 13 23 13 23 heart 18 12 12 17 19 0 0 euain oterma aus hslasto leads This values. mean their to regulations 16 20 a ● ● ● ● ● c ● ● ● ● 11 11 1 1 15 21 t i Bmal1 v Dbp 10 10 a 14 22 2 2 ● ● t ● o 9 3 9 3 r 13 23 ● y ● ● ● 8 4 8 4 ● ● ● 7 5 7 5 ● 6 6 12 0 ● 18 18 17 19 17 19 ● 16 20 16 20 11 β 1 15 21 15 21 i . brown adipose n 10 LSComput PLoS ● 2 14 22 14 22 h ● 485: Nature, i ● b ● 9 3 ● ● ● i ● 13 23 13 23 ● ● ● t ● ● ● ● aorta o 8 4 r 7 5 y 6 12 12 0 0 Nature, 14125 DOI: 10.3252/pso.eu.17ICSB.2016 11 11 1 1 52% 10 10 2 2 Gene Rev-erb- Cry1 Per2 Rev-erb- 9 3 9 3 Cry1 Per2 8 4 8 4 7 5 7 5 6 6 18 18 u-ewrsaeoclaigwt a with oscillating are sub-networks 17 19 17 19 α 16 20 16 20 [9] [8] [7] [6] 15 21 15 21 Dbp 50% α adrenal gland 14 22 14 22 ihiZege l ordnatrlso h Pr n Pr ee ntemmaincrainclock. circadian mammalian the in genes mPer2 and mPer1 the of roles 2001. Nonredundant 105:683–694, al. et Zheng Binhai gene circadian medicine. A and Hogenesch. biology B. for John 2014. implications and Hughes, mammals: E. in Michael atlas rhythms. Ballance, circadian I. expression Heather of Lahens, maintenance F. for Nicholas essential Zhang, are Ray Cry2 and Cry1 Mammalian 1999. al. 398:627–630, et Nature Horst , func- der clock van circadian J for T required Gijsbertus is 1 by repression feedback in tion. Delay al. et Ukai-Tadenuma Maki 52% 13 23 13 23 lung 18 17 19 12 12 16 20 0 0 15 21 4:6–8,2011. 144:268–281, Cell, 11 11 1 1 Per2

14 22 Gene Expression [a.u.] 1.5 0.5 2.5 10 10 2 2 3 2 1 13 23 0 liver 9 3 9 3 12 8 4 8 4 0 52% 7 5 7 5 6 6 11 18 18 12 1 100% 17 19 17 19 49% 16 20 16 20 10 2 15 21 15 21 Circadian Circadian Time [h] white adipose white 9 3 14 22 14 22 24 8 4 7 5 13 23 13 23 kidney 6 12 12 0 0 50% 36 Cry1 Per2 Rev− Dbp Bmal1 11 11 1 1 presented Poster 54% 10 10 2 2 48% 48 erb-α 9 9 3 3 8 8 4 4 7 7 5 5 6 6 60 131072 99% Cry1 at: 50% ldsamliueo diinlfeedbacks. literature additional the of multitude in a cludes debated that regulations [4] all created sents was model mathematical A ewr topology Network lmigacmiainof combination a clamping sub-networks, possible all neatos erdto ae n post- data. qPCR to been parameters fitted have and regulation unknown transcriptional describing rates delays; regulatory degradation transcriptional verified experimentally interactions, on based receptor nuclear the and regulator D-box the respectively, targets box includes , Dbp Dbp otalngtv edakloops feedback negative al- all connects most and regulators additional number via large links a of with coherent is repressilator The 49% ifrn sub-networks. different 50% eid fteentok,9%contain 97% networks, these Of period. 24h 50% Bmal1 97% Per2 Dbp Dbp Rev-erb- Per2 sadie fEbxmediated E-box of driver a as Rev-erb- 52% Bmal1 and α 111:16219–16224, A, S U Sci Acad Natl Proc Bmal1 Bmal1 +Dbp Bmal1 Dbp Dbp Cry1 Rev-Erba. 52% α seryadlt E- late and early as Cry1 Bmal1 +Dbp Bmal1 Bmal1 n in- and repre- Dbp Dbp Dbp Cell,