Retrotransposons en HIV: meer gelijkenissen dan gedacht?

Saskia
Lesire

De evolutie van de mens is een proces dat nog steeds aan de gang is. Verschillen in ons DNA zorgen voor diversiteit tussen individuen en maken ons vanuit darwinistisch perspectief meer aangepast aan onze leefomgeving. Retrotransposons zijn een van de drijvers van dit dynamisch proces. Hoewel ze hun belang hebben aangetoond in de evolutie van de mens, is over retrotransposons slechts het tipje van de ijsberg gekend. 

Al in 1948, nog voor de structuur van DNA ontdekt werd, deed Barbara McClintock onderzoek in genetica. Haar baanbrekende studie over mobiele stukjes DNA, die ze later transposons noemde, werd met veel ongeloof ontvangen. In die tijd werd immers gedacht dat DNA statisch was, en mobiele DNA fragmenten pasten de facto niet in dat plaatje. McClintock kreeg pas na lange tijd erkenning en uiteindelijk ook een Nobelprijs voor haar werk, dat tot op vandaag invloed heeft op onze kennis van het menselijk DNA. 

Springende genen in het menselijk DNA: een korte introductie

DNA is de drager van erfelijke informatie en bevindt zich in de kern van onze cellen. DNA wordt doorgegeven van generatie op generatie, maar ondergaat hierbij ook enkele veranderingen. Een van de mechanismen achter deze veranderingen is transpositie. Zoals de naam al doet vermoeden, zijn transposons fragmenten DNA die zich op een andere plek inbouwen in het DNA. Ze zijn beter bekend als ‘springende genen’ door hun vermogen om te ‘springen’ tussen verschillende locaties in het DNA. Op deze manier veranderen ze het erfelijk materiaal dat aan de volgende generatie wordt doorgegeven. 

Retrotransposons zijn een subcategorie van transposons. Ze werken via een kopieer-en-plak mechanisme, met als gevolg dat ons DNA steeds uitbreidt (zie figuur 1). Vergelijk het met een boek waarvan je een pagina kopieert en op een willekeurige plaats in het boek terugzet. Misschien zal het je verassen, maar wel 40% van ons DNA bestaat uit retrotransposons.

Figuur 1

Figuur 1: Retrotranspositie in de cel. 

Recent onderzoek toonde aan dat retrotransposons voornamelijk actief zijn in de hersenen en een rol spelen in geheugenvorming. Het proces van retrotranspositie heeft echter ook een keerzijde. De sprong van een retrotransposon naar een ongewenste plaats in ons DNA kan een waaier aan ziekten veroorzaken. Voorbeelden hiervan zijn kanker, Rett syndroom en schizofrenie. Steeds meer studies wijzen op het belang van een goede balans in het proces van retrotranspositie zodat het niet te weinig optreedt, maar vooral ook niet te veel. Doorheen de evolutie hebben onze cellen zich aangepast om dit proces onder controle te houden waardoor de schade doorgaans gelimiteerd blijft. 

Retrotranspositie: een proces met veel ontbrekende puzzelstukken

Hoewel het proces van retrotranspositie al langer gekend is, komen we nog veel kennis tekort over de exacte functie en het werkingsmechanisme van retrotransposons. Welke eiwitten hebben retrotransposons nodig om zich te verplaatsen? Welke eiwitten houden retrotransposons net tegen om te springen? Deze kennis hebben we nodig om te begrijpen hoe retrotransposons werken en wat er exact gebeurt wanneer het misloopt. 

Gelijkenissen tussen LINE-1 retrotransposons en HIV

LINE-1 retrotransposons zijn de enige transposons die nog steeds actief zijn in menselijke cellen. Hoewel LINE-1 retrotransposons van nature voorkomen in ons DNA, vertonen ze qua structuur sterke gelijkenissen met het humaan immunodeficiëntievirus (HIV), het virus dat aids veroorzaakt. HIV maakt gebruik van de aanwezige infrastructuur in de cel om zich te vermeerderen. Net zoals HIV hebben LINE-1 retrotransposons deze infrastructuur nodig om te kunnen springen. Deze interessante gelijkenis vormde het onderzoeksvraagstuk van mijn thesis. We bestudeerden eiwitten die een rol spelen bij een HIV infectie en onderzochten of deze ook een rol spelen in LINE-1 retrotranspositie. 

Het meten van retrotranspositieactiviteit

Voor ons onderzoek hebben we een methode geoptimaliseerd waarbij we de activiteit van het LINE-1 retrotransposon konden meten. Door het retrotransposon te labelen met een groen fluorescent eiwit, kregen cellen een groene kleur wanneer het LINE-1 retrotransposon ‘springt’. Daarna konden we meten hoeveel cellen in het staal groen kleuren. 

In een volgende stap werd er met behulp van biotechnologische hulpmiddelen één eiwit in de cel uitgeschakeld en konden we meten of dit een effect heeft op LINE-1 retrotranspositie (zie figuur 2). Wanneer we een stijging in het aantal groene cellen observeerden, had het eiwit een onderdrukkende functie. Omgekeerd, wanneer we een daling in het aantal groene cellen observeerden, had het eiwit een stimulerende functie. 

Figuur 2

Figuur 2: De LINE-1 retrotranspositie assay: een methode om LINE-1 activiteit in cellen te bestuderen.

Het eiwit LEDGF/p75 stimuleert LINE-1 retrotranspositie

HIV virussen zijn uniek doordat ze hun eigen virale DNA inbouwen in het DNA van de gastheercel. Het virus heeft hiervoor de hulp nodig van enkele eiwitten in de cel. Een van deze eiwitten is LEDGF/p75 dat bindt aan het viraal DNA en helpt bij de inbouwen in het gastheer DNA. Deze interactie maakt van LEDGF/p75 dan ook een veelbelovend doelwit bij de zoektocht naar een geneesmiddel tegen HIV. 

Vertrekkend vanuit de gelijkenissen tussen HIV en LINE-1 bestudeerden we de functie van LEDGF/p75 in LINE-1 retrotranspositie. De resultaten wezen erop dat LEDGF/p75 stimulerend werkte op LINE-1 retrotranspositie. LEDGF/p75 zorgt dus voor meer retrotranspositie in onze cellen. Een intrigerende bevinding die veel vragen oproept. In welke stap van de retrotranspositiecyclus speelt LEDGF/p75 een rol? Hoe interageert LEDGF/p75 met het retrotransposon? Zijn er nog andere eiwitten bij betrokken? De resultaten geven ons in ieder geval veel stof tot nadenken. 

De eerste stappen van een lange weg

Deze studie zet slechts de eerste stappen in het onderzoek naar eiwitten die een rol spelen in LINE-1 retrotranspositie. De overeenkomsten tussen LINE-1 en HIV dagen ons uit om dit verder te onderzoeken. Wellicht is de ontbrekende kennis over retrotransposons te vinden bij onze kennis over HIV. Momenteel moeten we echter genoegen nemen met het besef dat retrotranspositie in onze hersenen gebeurt zonder dat we er veel over weten. Misschien zijn retrotransposons net nodig om je dit artikel te kunnen herinneren? De toekomst zal het uitwijzen. 

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Universiteit of Hogeschool
KU Leuven
Thesis jaar
2020
Promotor(en)
Prof. Zeger Debyser