Livet hos varje organism, må det vara en bakterie eller en multicellulär organism såsom människan, kontrolleras uteslutande av aktiviteten hos celler. Cellkärnan innehåller nästan all information i form av DNA, genomet, som beskriver denna aktivitet. DNA-molekyler är strukturellt organiserade i två komplementära strängar av nukleotider i enheter av baspar. Alla dubbelsträngar av DNA i en cell, normalt sett 46 stycken hos människor, organiseras och packas i 22 par av kromosomer samt två könskromosomer. Genom kombinationer av nukleotider definieras funktionella enheter, gener, som beskriver sammansättningen av RNA vilket i sin tur kan beskriva hur proteiner konstrueras. Gener i sig innehåller funktionella element, exoner, som beskriver dess slutprodukt och kan kombineras på olika sätt genom så kallad splitsning. En gen har i sig ingen funktionell egenskap förutom som informationsbärare. Aktiviteten i celler styrs emellertid av dess produkter; RNA eller protein.
En människa består av flera miljarder celler vilka kan grupperas i över 200 olika celltyper. Vissa celltyper existerar och har samma roll i flera organ medan andra har specifika egenskaper och är begränsade till enstaka organ. På samma sätt avläses informationen hos vissa gener i alla celltyper medan andra gener endast används i ett fåtal celltyper. Ändå, med vissa undantag av celltyp och variation i DNA, så är genomet detsamma i alla celler hos en individ. Även om kontrollen av genaktivitet är kodat i DNA så skiljer sig dess reglering åt mellan celltyper och under olika faser av en cells livscykel.
Genaktivitet styrs i två separerbara nivåer. Den strukturella och kemiska signaturen hos regioner i DNA påverkas av dess kombination av nukleotider och eventuella kemiska modifieringar, den första nivån av genreglering. Följaktligen kan dessa egenskaper påverka möjligheten för proteiner med genreglerande egenskaper att binda till DNA. Transkriptionsfaktorer innefattas i denna typ av DNA-bindande proteiner, vilka kan styra rekryteringen av det maskineri av proteiner som behövs för avläsning, transkription, av gener.
I den andra nivån, den strukturella nivån av genreglering, styrs geners aktivitet av högre organisation och packning av DNA i kromosomer. För att få plats i cellkärnan måste DNA packas extremt väl. Nukleosomer, komplex av histonproteiner med DNA virat kring sig, utgör grunden för sådan packning. Packningen påverkas även av kemiska modifieringar, så kallade histonmodifieringar, och internukleosomala interaktioner vilket resulterar i
olika tillstånd av kromatin. Nivån av packning varierar mellan olika regioner i DNA vilket påverkar dess möjlighet att binda regulatoriska proteiner eller åtkomsten av gener för transkriptionsmaskineriet. Den strukturella organisationen påverkar även avståndet mellan regulatoriska element och gener vilket kan påverka deras regulatoriska kapacitet. Celler med onormal kromosomorganisation, t.ex. via kromosomala dupliceringar eller deletioner, eller onormal packning av kromatin kan följaktligen få onormal regulatorisk aktivitet. Detta kan slutligen resultera i onormal transkriptionell aktivitet. Cancerceller är exempel på celler med onormal aktivitet.
För att förstå hur genreglering påverkas av kromatiska eller onormala kromosomala tillstånd krävs storskaliga biologiska experiment sammanlänkade med sofistikerade bioinformatiska metoder vilket möjliggör mätningen av sådana egenskaper i hela genomet. Analys av genreglering genom kromatin innefattar kartläggning av nukleosomers positioner, dess modifieringar samt hur position eller status påverkar geners uttryck eller hur dessa egenskaper i sig påverkas av faktorer, t.ex. externa stimuli, vilka ändrar cellers tillstånd och aktivitet. Kromosomala avvikelser kan vara gemensamma eller skilja sig väsentligt mellan olika cancertyper. För att förstå vilka gener vars uttryck särskiljer en cancercell från en frisk sådan krävs kartläggning av deras omslutande kromosomala avvikelser.
I denna avhandling presenteras bioinformatiska verktyg och resultaten av deras användande på storskaliga biologiska data för att förstå genreglering genom kromatin och kromosomala avvikelser. Genom användandet av ett flertal datakällor från mätningar av olika egenskaper hos celler har frågeställningar angripits på ett kombinerat sätt (Paper I, Paper II & Paper IV). Detta angreppssätt har gjort det möjligt att testa existerande hypoteser, såsom nukleosomers positioneringspotential över exoner och hur en sådan positionering kan påverka geners uttryck (Paper I & Paper II). Vi har även genererat nya hypoteser inom grundläggande molekylärbiologi (Paper I, Paper II & Paper IV) vilka kräver uppföljande studier. Statistiska metoder i vilka man kan inkorporera bakgrundskunskap och vars modeller kan anpassas till data har lämpat sig väldigt bra i våra studier. Användandet av dessa metoder har lett till precisa prediktioner av kromosomala brytpunkter i cancergenom (Paper III & Paper IV) samt pålitliga positioneringar av nukleosomer och dess förflyttningar under transkriptionell reglering (Paper II).
Våra resultat har visat att kromatin spelar en viktig roll i regleringen av geners transkription. Vi har visat att nukleosomer har en stark preferens för exoner och att deras position i sådana regioner ej påverkas nämnvärt av geners aktivitet (Paper I & Paper II). Detta antyder att positioneringen av nukleosomer över exoner, dock med marginella skillnader mellan enskilda celler (Paper II), har en viktig roll eftersom denna preferens bevarats genom evolutionen (Paper I). Faktum är att vissa histonmodifieringar visade sig starkt kopplade till exoniska nukleosomer och indikerade användandet av
enskilda exoner i transkription av en gen (Paper I) vilket tyder på en roll i splitsning. Dessutom verkade nukleosomers positionering vara viktig och deras förflyttning vara frekvent förekommande i regleringen av transkriptionsfaktorers åtkomst till DNA (Paper II).
Histonmodifieringar kan också spela en avgörande roll vid förändrad transkriptionell aktivitet. Våra resultat visar att antingen histonmodifieringar eller kromosomala avvikelser, eller bådadera, utgör den bakomliggande orsaken till förändrat uttryck hos flertalet gener i cancerceller (Paper IV). Genom en kombinerad analys av flera datakällor kunde vi härleda möjliga, både kända och okända, gener associerade med cancer.
Acknowledgements
To state that others have influenced the work presented in this thesis would be a great underestimation. I am in great dept to numerous people for invaluable knowledge, expertise, opinions, support, guidance and friendship making this thesis a reality.
Many thanks are due to
Professor Jan Komorowski, my main advisor. Thank you for scientific guidance and for encouraging me to (almost unrestrictedly) explore the world of biology and medicine and mine their wealth in data. I am very grateful for you trusting my capabilities.
Professor Jan Dumanski, my co-advisor. Our collaborative projects have been challenging but fun. I really appreciate your scientific visions and eagerness to conduct rigorous research.
Professor Claes Wadelius, my co-advisor. Thank you for introducing me to the field of chromatin, for numerous research ideas, support, guidance and for putting me on the right track when I think I understand something but obviously do not.
Professor emeritus Jan Maluszynski, former master thesis supervisor at Linköping University, for being the initiating factor for me starting my PhD studies. I will always remember your encouragements and care.
Former (Torgeir, Alice, Claes, Helena, Jakub, Eva, Adam, Marcin,
Aleksejs, Alvaro, Alvaro (yes there were two of them) and Olle) and present (Stefan, Marcin (not the former one), Susanne and Henric) colleagues at the Linnaeus Centre for Bioinformatics. I am especially grateful for scientific and non-scientific discussions as well as explorations in (sometimes rather obscure) music history held within the Aquarium (Stefan, Jakub and Adam).
Former and present members of the Jan Dumanski/Teresita Diaz de Ståhl group. Thank you (especially Johanna, Helena, Tere, Calle, Arek and
Uwe) for good collaborations and for providing me with a lot of challenging work during my first years as a PhD student.
Former and present members (Madhu, Mehdi, Ola and Alvaro (again)) of the Claes Wadelius group as well as the participants of the Chromatin Journal club (especially Chandrasekhar Kanduri and his gang in addition to the ones mentioned above) for vivid (and rather detailed) discussions regarding chromatin biology.
The administrative staff (Gunilla, Sigrid and Christin) for invaluable support.
The folks at the BMC Computer Department (Nils-Einar, Emil, Gustavo,
Anders and Jerker) for maintenance of servers and supporting our needs.
Inge, Elna, Jim, Maria and Povel. Thank you for everlasting support and encouragements during these years and for letting me try over and over again to explain what I really do in plain Swedish.
Bosse, Lotta, Sanna, Kjetil and Jenna for great support during this process. I really appreciate you helping me and my family out when the schedules were too heavy.
Emma, my love. Without your support and encouragements not a word in this thesis would have been written. A simple thank you is not enough. I am very grateful for you being at my side during all those years. A special “tack så mycket” (or “takto” in his own words) to my wonderful son Lowe for constantly reminding me of what is important in life.
Robin Andersson Uppsala, September 2010
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