Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth
Abstract Background Preterm birth is defined as live birth before 37 completed weeks of pregnancy, and it is a major problem worldwide. The molecular mechanisms that lead to onset of spontaneous preterm birth are incompletely understood. Prediction and evaluation of the risk of preterm birth is chal...
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| Format: | Article |
| Language: | English |
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BMC
2022-04-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-022-02339-8 |
| _version_ | 1817976300705415168 |
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| author | Heli Tiensuu Antti M. Haapalainen Pinja Tissarinen Anu Pasanen Tomi A. Määttä Johanna M. Huusko Steffen Ohlmeier Ulrich Bergmann Marja Ojaniemi Louis J. Muglia Mikko Hallman Mika Rämet |
| author_facet | Heli Tiensuu Antti M. Haapalainen Pinja Tissarinen Anu Pasanen Tomi A. Määttä Johanna M. Huusko Steffen Ohlmeier Ulrich Bergmann Marja Ojaniemi Louis J. Muglia Mikko Hallman Mika Rämet |
| author_sort | Heli Tiensuu |
| collection | DOAJ |
| description | Abstract Background Preterm birth is defined as live birth before 37 completed weeks of pregnancy, and it is a major problem worldwide. The molecular mechanisms that lead to onset of spontaneous preterm birth are incompletely understood. Prediction and evaluation of the risk of preterm birth is challenging as there is a lack of accurate biomarkers. In this study, our aim was to identify placental proteins that associate with spontaneous preterm birth. Methods We analyzed the proteomes from placentas to identify proteins that associate with both gestational age and spontaneous labor. Next, rare and potentially damaging gene variants of the identified protein candidates were sought for from our whole exome sequencing data. Further experiments we performed on placental samples and placenta-associated cells to explore the location and function of the spontaneous preterm labor-associated proteins in placentas. Results Exome sequencing data revealed rare damaging variants in SERPINA1 in families with recurrent spontaneous preterm deliveries. Protein and mRNA levels of alpha-1 antitrypsin/SERPINA1 from the maternal side of the placenta were downregulated in spontaneous preterm births. Alpha-1 antitrypsin was expressed by villous trophoblasts in the placenta, and immunoelectron microscopy showed localization in decidual fibrinoid deposits in association with specific extracellular proteins. siRNA knockdown in trophoblast-derived HTR8/SVneo cells revealed that SERPINA1 had a marked effect on regulation of the actin cytoskeleton pathway, Slit–Robo signaling, and extracellular matrix organization. Conclusions Alpha-1 antitrypsin is a protease inhibitor. We propose that loss of the protease inhibition effects of alpha-1 antitrypsin renders structures critical to maintaining pregnancy susceptible to proteases and inflammatory activation. This may lead to spontaneous premature birth. |
| first_indexed | 2024-04-13T22:01:46Z |
| format | Article |
| id | doaj.art-04242490e6fe48ffa80aef8110c60e46 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-13T22:01:46Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-04242490e6fe48ffa80aef8110c60e462022-12-22T02:28:04ZengBMCBMC Medicine1741-70152022-04-0120112310.1186/s12916-022-02339-8Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birthHeli Tiensuu0Antti M. Haapalainen1Pinja Tissarinen2Anu Pasanen3Tomi A. Määttä4Johanna M. Huusko5Steffen Ohlmeier6Ulrich Bergmann7Marja Ojaniemi8Louis J. Muglia9Mikko Hallman10Mika Rämet11PEDEGO Research Unit and Medical Research Center Oulu, University of OuluPEDEGO Research Unit and Medical Research Center Oulu, University of OuluPEDEGO Research Unit and Medical Research Center Oulu, University of OuluPEDEGO Research Unit and Medical Research Center Oulu, University of OuluPEDEGO Research Unit and Medical Research Center Oulu, University of OuluPEDEGO Research Unit and Medical Research Center Oulu, University of OuluProteomics and Mass Spectrometry Core Facilities, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of OuluProteomics and Mass Spectrometry Core Facilities, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of OuluPEDEGO Research Unit and Medical Research Center Oulu, University of OuluDivision of Human Genetics, Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, March of Dimes Prematurity Research Center Ohio CollaborativePEDEGO Research Unit and Medical Research Center Oulu, University of OuluPEDEGO Research Unit and Medical Research Center Oulu, University of OuluAbstract Background Preterm birth is defined as live birth before 37 completed weeks of pregnancy, and it is a major problem worldwide. The molecular mechanisms that lead to onset of spontaneous preterm birth are incompletely understood. Prediction and evaluation of the risk of preterm birth is challenging as there is a lack of accurate biomarkers. In this study, our aim was to identify placental proteins that associate with spontaneous preterm birth. Methods We analyzed the proteomes from placentas to identify proteins that associate with both gestational age and spontaneous labor. Next, rare and potentially damaging gene variants of the identified protein candidates were sought for from our whole exome sequencing data. Further experiments we performed on placental samples and placenta-associated cells to explore the location and function of the spontaneous preterm labor-associated proteins in placentas. Results Exome sequencing data revealed rare damaging variants in SERPINA1 in families with recurrent spontaneous preterm deliveries. Protein and mRNA levels of alpha-1 antitrypsin/SERPINA1 from the maternal side of the placenta were downregulated in spontaneous preterm births. Alpha-1 antitrypsin was expressed by villous trophoblasts in the placenta, and immunoelectron microscopy showed localization in decidual fibrinoid deposits in association with specific extracellular proteins. siRNA knockdown in trophoblast-derived HTR8/SVneo cells revealed that SERPINA1 had a marked effect on regulation of the actin cytoskeleton pathway, Slit–Robo signaling, and extracellular matrix organization. Conclusions Alpha-1 antitrypsin is a protease inhibitor. We propose that loss of the protease inhibition effects of alpha-1 antitrypsin renders structures critical to maintaining pregnancy susceptible to proteases and inflammatory activation. This may lead to spontaneous premature birth.https://doi.org/10.1186/s12916-022-02339-8Alpha-1-antitrypsinPlacentaProteomicsPreterm birthSERPINA1Trophoblast |
| spellingShingle | Heli Tiensuu Antti M. Haapalainen Pinja Tissarinen Anu Pasanen Tomi A. Määttä Johanna M. Huusko Steffen Ohlmeier Ulrich Bergmann Marja Ojaniemi Louis J. Muglia Mikko Hallman Mika Rämet Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth BMC Medicine Alpha-1-antitrypsin Placenta Proteomics Preterm birth SERPINA1 Trophoblast |
| title | Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth |
| title_full | Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth |
| title_fullStr | Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth |
| title_full_unstemmed | Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth |
| title_short | Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth |
| title_sort | human placental proteomics and exon variant studies link aat serpina1 with spontaneous preterm birth |
| topic | Alpha-1-antitrypsin Placenta Proteomics Preterm birth SERPINA1 Trophoblast |
| url | https://doi.org/10.1186/s12916-022-02339-8 |
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