Genome structural variation modulating the placenta and pregnancy maintenance
Failid
Kuupäev
2018-04-06
Autorid
Ajakirja pealkiri
Ajakirja ISSN
Köite pealkiri
Kirjastaja
Abstrakt
Ema ja loote vaheline suhtlus loob aluse raseduse edukaks kulgemiseks. Rasedus on naise jaoks füsioloogiline väljakutse, mida kinnitab nii varaste (korduv raseduse katkemine, KRK) kui hiliste (preeklampsia, gestatsioonidiabeet, raseduskestuse kohta suur/väike sünnikaal) rasedustüsistuste rohkus. Rasedusaegseid komplikatsioone on sageli seostatud puuduliku platsenta invasiooni ning funktsiooniga, seetõttu on äärmiselt oluline täielik arusaam platsenta bioloogiast. Platsenta geenide avaldumise tase ja dünaamika reguleerib platsenta funktsiooni ja seeläbi raseduse kulgemist. Inimese platsenta RNA molekulide profiili moduleerib geneetiline varieeruvus, millest kõige enam on uuritud ühenukleotiidseid muutusi.
Käesolevas doktoritöös uuriti esmakordselt DNA koopiaarvu muutuste (copy number variation, CNV) mõju teadmata põhjusega KRK (=>3 järjestikust raseduse katkemist) tekkes. CNV-d põhjustavad nähtust, kus teatud genoomi osad on kustutatud ja teistest on tehtud lisakoopiaid. CNV-sid on seostatud mitmete erinevate haigustega, kuid vähe on uuringuid rasedustüsistuste vallas. Kogu genoomi CNV piirkondade uuring Eesti ja Taani valimites tuvastas lisakoopia ehk duplikatsiooni 5. kromosoomil, mis suurendab KRK riski naistel ligi viis korda. Antud duplikatsioon hõlmab kahte platsentas kõrgelt avaldunud geeni (PDZD2 ja GOLPH3), mida pole varasemalt rasedusega seostatud. Lisauuringus leiti, et KRK vanemate genoomides leidub enam pikki kromosoomide otste ja keskmete läheduses asuvaid muutusi, mis võivad soosida vigu kromosoomide normaalsel jagunemisel.
Lisaks võrreldi kogu genoomi CNV-de profiili vanemate verest ja platsentast eraldatud DNA-s nii normaalse raseduse erinevatel trimestritel kui rasedustüsistuste korral. Tulemused näitavad, et raseduse edukaks kulgemiseks ajab platsenta oma rakkude genoomi sassi justkui vähkkasvaja. Seetõttu esineb platsenta genoomis suurel hulgal muutusi, eelkõige duplikatsioone: ligi kuus korda enam kui vanematel genoomis. Kui aga ümberkorraldusi on liiga vähe, võivad tekkida mitmed rasedusaegsed komplikatsioonid. Duplikatsioonid hõlmasid geene, mis on seotud embrüonaalse arenguga ja platsenta rakkude invasiooni toetava protsessiga. See viitab sellele, et platsenta genoomis toimunud muutused soodustavad organi tööd ja raseduse edukat kulgemist.
The establishment and maintenance of pregnancy relies on the well-coordinated crosstalk between the mother and the embryo. Pregnancy is an enormous physiological challenge a woman can experience and can cause early (recurrent pregnancy loss, RPL) as well as late (preeclampsia, gestational diabetes mellitus and fetal growth abnormalities) gestational complications. As these complications are often associated with poor trophoblast invasion and placental function, there is an urgent need for complete understanding of placental biology. Placental gene expression levels and dynamics regulate the function of placenta and therefore pregnancy maintenance. Transcriptome of the human placenta is modulated by genetic variation of which single nucleotide variants have been investigated the most. The experimental part of the thesis explored the role of DNA copy number variation (CNV) in idiopathic RPL (=>3 consecutive pregnancy losses). CNVs represent a phenomenon where parts of the genome are missing or duplicated. CNVs have been implicated in various human diseases; however, studies are lacking in reproductive disorders. Genome-wide CNV profiling of parental genomes of Estonian and Danish couples with recurrent pregnancy loss discovered a duplication on chromosome 5 increasing maternal risk of RPL up to 5 times. The duplication encompasses two genes (PDZD2 and GOLPH3) with enhanced expression in placenta and associated with pregnancy maintenance for the first time. Further research detected overrepresentation of large pericentromeric and subtelomeric CNVs in RPL parental genomes that may promote errors in normal chromosome segregation. Additionally, a comparison of genome-wide CNV profiles of parental and placental genomes of three trimesters of normal gestations as well as pregnancy complications was conducted. Similarly to cancer genomes, an extensive load of CNVs was detected as a hallmark of normal placental development. The load was mostly caused by the number of duplications, which were enriched in genes relevant to embryonic development. Early as well as late pregnancy complications showed reduced capacity to promote somatic genomic rearrangements in the placenta. The results indicate that the extensive amount of changes in the placental genome contributes to placental function and successful maintenance of pregnancy.
The establishment and maintenance of pregnancy relies on the well-coordinated crosstalk between the mother and the embryo. Pregnancy is an enormous physiological challenge a woman can experience and can cause early (recurrent pregnancy loss, RPL) as well as late (preeclampsia, gestational diabetes mellitus and fetal growth abnormalities) gestational complications. As these complications are often associated with poor trophoblast invasion and placental function, there is an urgent need for complete understanding of placental biology. Placental gene expression levels and dynamics regulate the function of placenta and therefore pregnancy maintenance. Transcriptome of the human placenta is modulated by genetic variation of which single nucleotide variants have been investigated the most. The experimental part of the thesis explored the role of DNA copy number variation (CNV) in idiopathic RPL (=>3 consecutive pregnancy losses). CNVs represent a phenomenon where parts of the genome are missing or duplicated. CNVs have been implicated in various human diseases; however, studies are lacking in reproductive disorders. Genome-wide CNV profiling of parental genomes of Estonian and Danish couples with recurrent pregnancy loss discovered a duplication on chromosome 5 increasing maternal risk of RPL up to 5 times. The duplication encompasses two genes (PDZD2 and GOLPH3) with enhanced expression in placenta and associated with pregnancy maintenance for the first time. Further research detected overrepresentation of large pericentromeric and subtelomeric CNVs in RPL parental genomes that may promote errors in normal chromosome segregation. Additionally, a comparison of genome-wide CNV profiles of parental and placental genomes of three trimesters of normal gestations as well as pregnancy complications was conducted. Similarly to cancer genomes, an extensive load of CNVs was detected as a hallmark of normal placental development. The load was mostly caused by the number of duplications, which were enriched in genes relevant to embryonic development. Early as well as late pregnancy complications showed reduced capacity to promote somatic genomic rearrangements in the placenta. The results indicate that the extensive amount of changes in the placental genome contributes to placental function and successful maintenance of pregnancy.
Kirjeldus
Väitekirja elektrooniline versioon ei sisalda publikatsioone