Extensive shift in placental transcriptome profile in preeclampsia and placental origin of adverse pregnancy outcomes

One in five pregnant women suffer from gestational complications, prevalently driven by placental malfunction. Using RNASeq, we analyzed differential placental gene expression in cases of normal gestation, late-onset preeclampsia (LO-PE), gestational diabetes (GD) and pregnancies ending with the birth of small-for-gestational-age (SGA) or large-for-gestational-age (LGA) newborns (n = 8/group). In all groups, the highest expression was detected for small noncoding RNAs and genes specifically implicated in placental function and hormonal regulation. The transcriptome of LO-PE placentas was clearly distinct, showing statistically significant (after FDR) expressional disturbances for hundreds of genes. Taqman RT-qPCR validation of 45 genes in an extended sample (n = 24/group) provided concordant results. A limited number of transcription factors including LRF, SP1 and AP2 were identified as possible drivers of these changes. Notable differences were detected in differential expression signatures of LO-PE subtypes defined by the presence or absence of intrauterine growth restriction (IUGR). LO-PE with IUGR showed higher correlation with SGA and LO-PE without IUGR with LGA placentas. Whereas changes in placental transcriptome in SGA, LGA and GD cases were less prominent, the overall profiles of expressional disturbances overlapped among pregnancy complications providing support to shared placental responses. The dataset represent a rich catalogue for potential biomarkers and therapeutic targets.Peer reviewe

Platsenta transkriptoom ja miRNoom tervete ja komplikatsioonidega raseduste korral

Väitekirja elektrooniline versioon ei sisalda publikatsiooneIga raseduse kulg on unikaalne aga iga ema soov on see läbida komplikatsioonideta ning saada endale täie tervise juures vastsündinu. Palju oleneb raseda elustiilist ja geneetikast millise tulemini jõutakse. Ma saame elustiili harjumusi muuta ja parandada aga geneetikaga saame hinnata võimalike probleemide riske. Selle jaoks vajame täpseid teadmisi kuidas platsentas geenide ja mikroRNAde ekspressioon on reguleeritud. Platsenta töötab kui ema ja loote vaheline suhtlusvahend, reguleerides hapniku ja toitainete transporti lootele ja sealsete jääkainete eemaldamist. Platsenta kasv on kiire ning selle jaoks on vajalik täpne geenide ekspressiooni taseme regulatsioon, et tagada lootele võimalikult soodne kasvukeskkond. Üheks geenide ekspressiooni regulaatoriteks on mikroRNAd, mis võimaldavad kiiresti reguleerida geenide ekspressiooni taset. Käesolev uuring keskendus geenide ja mikroRNAde profiili uurimisele platsenta koes tervete ja komplikatsioonidega raseduste korral. Lisaks hindasime millised regulaatorid on veel olulised mikroRNAde ekspressiooni taseme muutuseks. Leidsime, et preeklampsia korral on platsentas muutunud suurel hulgal geenide (n=215) ja mikroRNAde (n=66) ekspressiooni tase võrreldes normaalsete platsentadega. Lisaks leidsime, et tulenevalt gestatsiooni ajast on mikroRNAdel varieeruv ekspressiooni profiil. Platsenta spetsiifiliste mikroRNAde analüüsimisel leidsime, et vastavalt mikroRNA klastrile on neil kindel gestatsiooni ajast tingitud ekspressioon. Geenide ja mikroRNAde ekspressiooni andmestikku omavahelisel võrdlusel, leidsime nende vahelise tugeva seose, mis võimaldas mikroRNAd grupeerida funktsiooni alusel. Andmete analüüs, mis kasutab ühiselt nii geenide kui mikroRNAde ekspressiooni andmeid annab meile parema ülevaate kuidas erinevad raseduskomplikatsioonid mõjutavad geenide ja mikroRNAde ekspressiooni muutust.Every pregnancy is unique, but every mother’s dream is to have an uncomplicated pregnancy and a healthy newborn. Lifestyle and genetics are crucial factors for determining pregnancy outcomes. It is possible to adjust lifestyle, in the case of genetics, we can measure risk factors and mitigate their effect. We have the need to precisely understand how placental gene and microRNA expression regulates placenta function. The placenta connects the mother with the developing fetus, functioning as a nutrient exchange hub, supplying the fetus with nutrients and oxygen and removing waste products. Placenta development is fast and requires precise gene expression regulation for optimal fetal growth. MicroRNAs are small RNA molecules that regulate gene expression. This codependence is an informative study subject. This thesis aimed to analyze placental gene and microRNA expression in normal and complicated pregnancies and identify what could regulate their expression levels. Our findings show that in case of preeclampsia, gene and microRNA expression is shifted in placenta compared to normal pregnancy placentas (n=215 gene and n=66 microRNAs are differentially expressed). Describing microRNAs expression profiles in the context of gestation, we identified a distinct shift based on gestational progression. Placenta-specific microRNAs showed a similar expression change based on the cluster they are from. We found that microRNAs can be grouped based on their function when combining gene and microRNA expression datasets and evaluating their correlation. This kind of research gives more in-depth information on how placental gene and microRNA expression is regulated in different conditions and adds better understanding of gene and microRNA interactions.https://www.ester.ee/record=b555866

CDH13 geeni promootorala varieeruvuse seos südame- ja veresoonkonna tööd iseloomustavate parameetritega

2018-06-0

Sequenced placenta, serum and urine miRNomes of three healthy pregnancies

Sequenced miRNomes of the placenta, serum, and urine samples from three healthy pregnant females. Samples are collected from the third trimester