Placental gene expression in normal and complicated pregnancy
Date
2013-03-22
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Abstract
Platsenta on organ, mille kaudu on loode ühendatud ema organismiga. Raseduse jooksul osaleb platsenta loote ja ema ainevahetuses, sekreteerib rasedushormoone ning kaitseb arenevat beebit ema immuunsüsteemi ning välistegurite eest. Platsenta toimimiseks on vajalik täpne ajaline ja ruumiline platsenta geenide avaldumine. Seni on platsenta geeniekspressiooni dünaamika ning rasedustüsistustega seotud molekulaarsed mehhanismid põhjalikult kaardistamata.
Käesolev doktoriväitekiri käsitleb platsenta geeniekspressiooni kahest vaatenurgast. Esiteks uuritakse embrüo implantatsiooniks ning raseduse varajaseks säilitamiseks olulise koorionkonadotropiini hormooni (hCG) -alaühikut kodeerivate CGB geenide avaldumist platsentas. Töös kirjeldatakse CGB geenide ekspressioon läbi raseduse ning näidatakse, et piisava hCG taseme tagamiseks on vajalik mõlemalt vanemalt päritud geenialleelide avaldumine. Korduva spontaanabordi juhte iseloomustab oluliselt langenud CGB geenide ekspressioon. Lisaks leiti kolmel patsiendil isalt päritud CGB alleelide vaigistamine DNA metülatsiooni vahendusel. Neil juhtudel avaldusid platsentas vaid emalt päritud alleelid, mis võis viia hCG taseme languseni ema veres ning põhjustada raseduse katkemise.
Töö teises osas uuriti mikrokiipide abil globaalset platsenta geeniekspressiooni dünaamikat varajasest rasedusest raseduse keskpaigani. Leiti mitmed geenid, mille ekspressioon platsentas on kõrgeim raseduse keskpaigas. Lisaks tuvastati häired nende geenide avaldumises ema preeklampsia, gestatsiooni diabeedi ning loote kasvuanomaaliatega seotud platsentades. Sanniokaltsiin 1 (STC1) on uus potentsiaalne biomarker, mille taseme tõus ema veres on mõõdetav preeklampsia ja loote kasvupeetuse patsientidel. Töös kirjeldatud raseduse keskpaigas platsentas avalduvad geenid on lisaks seotud täiskasvanuea krooniliste haigustega, mis viitab üsasisese arengu rollile sünnijärgse tervise kujundamisel.
Kuna rahvastiku kasv ja vananev elanikkond mõjutavad ühiskonda järjest enam, on tööea pikendamine haiguste ennetamise teel üks tuleviku teaduse ja meditsiini väljakutsetest. Platsenta mõjutab ema ja loote heaolu nii raseduse ajal kui ka nende edasises elus. Seega omab platsenta geeniregulatsiooni mõistmine normaalses ja komplitseeritud raseduses suurt kliinilist ja sotsiaalset tähtsust.
Placenta is a unique temporary feto-maternal endocrine organ that mediates interactions between the mother and the fetus during gestation. Successful pregnancy requires spatial and temporal regulation of molecular, histological and functional changes in placenta to guarantee fetal growth and development as well as maternal adaptation to pregnancy. Despite its leading role in shaping in utero environment, the temporal dynamics of placental gene expression remains under-investigated. In this doctoral thesis, transcriptional and epigenetic regulation of placental gene expression was compared in normal and complicated pregnancies, and genes with altered transcription in pregnancy complications were identified. The first part of the thesis involved in-depth expression analysis of the CGB genes encoding the placental human chorionic gonadotropin (HCG). The HCG hormone is essential for embryo implantation, placentation, and maintenance of early pregnancy. The study described CGB transcription during normal pregnancy, and demonstrated that both parental CGB alleles are required for sufficient production of HCG. In contrast, cases of recurrent miscarriage showed significantly decreased CGB transcription in first trimester placentas compared to normal controls. Monoallelic maternal expression and promoter hemimethylation was detected in one normal and two complicated samples. The second part of the thesis involved transcriptional profiling of human placentas of early and mid-term pregnancies, and revealed genes with specific up-regulation during mid-gestation. Aberrant expression of mid-gestation placental genes was associated to pregnancy complications such as restricted fetal growth, maternal preeclampsia and gestational diabetes mellitus. The study highlighted the stanniocalcin-1 (STC1) protein as a novel prognostic biomarker for non-invasive determination of preeclampsia and restricted fetal growth from maternal serum. All complication-associated mid-gestation placental genes have been previously linked to adult complex diseases, emphasizing the role of placenta in developmental programming and in utero origin of adult disease. In summary, in utero development has a central role in determining the health of the child and the mother during pregnancy and also in their later lives. As the growth and aging of the global human population increasingly impact the society, disease prevention and extension of working age are important challenges of future science and medicine. Thus, understanding the role of placenta in healthy and complicated pregnancies is of great clinical and societal importance.
Placenta is a unique temporary feto-maternal endocrine organ that mediates interactions between the mother and the fetus during gestation. Successful pregnancy requires spatial and temporal regulation of molecular, histological and functional changes in placenta to guarantee fetal growth and development as well as maternal adaptation to pregnancy. Despite its leading role in shaping in utero environment, the temporal dynamics of placental gene expression remains under-investigated. In this doctoral thesis, transcriptional and epigenetic regulation of placental gene expression was compared in normal and complicated pregnancies, and genes with altered transcription in pregnancy complications were identified. The first part of the thesis involved in-depth expression analysis of the CGB genes encoding the placental human chorionic gonadotropin (HCG). The HCG hormone is essential for embryo implantation, placentation, and maintenance of early pregnancy. The study described CGB transcription during normal pregnancy, and demonstrated that both parental CGB alleles are required for sufficient production of HCG. In contrast, cases of recurrent miscarriage showed significantly decreased CGB transcription in first trimester placentas compared to normal controls. Monoallelic maternal expression and promoter hemimethylation was detected in one normal and two complicated samples. The second part of the thesis involved transcriptional profiling of human placentas of early and mid-term pregnancies, and revealed genes with specific up-regulation during mid-gestation. Aberrant expression of mid-gestation placental genes was associated to pregnancy complications such as restricted fetal growth, maternal preeclampsia and gestational diabetes mellitus. The study highlighted the stanniocalcin-1 (STC1) protein as a novel prognostic biomarker for non-invasive determination of preeclampsia and restricted fetal growth from maternal serum. All complication-associated mid-gestation placental genes have been previously linked to adult complex diseases, emphasizing the role of placenta in developmental programming and in utero origin of adult disease. In summary, in utero development has a central role in determining the health of the child and the mother during pregnancy and also in their later lives. As the growth and aging of the global human population increasingly impact the society, disease prevention and extension of working age are important challenges of future science and medicine. Thus, understanding the role of placenta in healthy and complicated pregnancies is of great clinical and societal importance.
Description
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Keywords
rasedus, platsenta, geeniekspressioon, gonadotroopsed hormoonid, pregnancy, placenta, gene expression, gonadotropins