Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders
Abstract Background Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neuronal disorders and birth defects. We hypothesize that early alcohol-induced epigenetic changes disrupt the accurate developmental programmin...
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| Format: | Article |
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BMC
2022-12-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-022-02699-1 |
| _version_ | 1797973586985615360 |
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| author | P. Auvinen J. Vehviläinen H. Marjonen V. Modhukur J. Sokka E. Wallén K. Rämö L. Ahola A. Salumets T. Otonkoski H. Skottman M. Ollikainen R. Trokovic H. Kahila N. Kaminen-Ahola |
| author_facet | P. Auvinen J. Vehviläinen H. Marjonen V. Modhukur J. Sokka E. Wallén K. Rämö L. Ahola A. Salumets T. Otonkoski H. Skottman M. Ollikainen R. Trokovic H. Kahila N. Kaminen-Ahola |
| author_sort | P. Auvinen |
| collection | DOAJ |
| description | Abstract Background Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neuronal disorders and birth defects. We hypothesize that early alcohol-induced epigenetic changes disrupt the accurate developmental programming of embryo and consequently cause the complex phenotype of developmental disorders. To explore the etiology of FASD, we collected unique biological samples of 80 severely alcohol-exposed and 100 control newborns at birth. Methods We performed genome-wide DNA methylation (DNAm) and gene expression analyses of placentas by using microarrays (EPIC, Illumina) and mRNA sequencing, respectively. To test the manifestation of observed PAE-associated DNAm changes in embryonic tissues as well as potential biomarkers for PAE, we examined if the changes can be detected also in white blood cells or buccal epithelial cells of the same newborns by EpiTYPER. To explore the early effects of alcohol on extraembryonic placental tissue, we selected 27 newborns whose mothers had consumed alcohol up to gestational week 7 at maximum to the separate analyses. Furthermore, to explore the effects of early alcohol exposure on embryonic cells, human embryonic stem cells (hESCs) as well as hESCs during differentiation into endodermal, mesodermal, and ectodermal cells were exposed to alcohol in vitro. Results DPPA4, FOXP2, and TACR3 with significantly decreased DNAm were discovered—particularly the regulatory region of DPPA4 in the early alcohol-exposed placentas. When hESCs were exposed to alcohol in vitro, significantly altered regulation of DPPA2, a closely linked heterodimer of DPPA4, was observed. While the regulatory region of DPPA4 was unmethylated in both control and alcohol-exposed hESCs, alcohol-induced decreased DNAm similar to placenta was seen in in vitro differentiated mesodermal and ectodermal cells. Furthermore, common genes with alcohol-associated DNAm changes in placenta and hESCs were linked exclusively to the neurodevelopmental pathways in the enrichment analysis, which emphasizes the value of placental tissue when analyzing the effects of prenatal environment on human development. Conclusions Our study shows the effects of early alcohol exposure on human embryonic and extraembryonic cells, introduces candidate genes for alcohol-induced developmental disorders, and reveals potential biomarkers for prenatal alcohol exposure. |
| first_indexed | 2024-04-11T04:06:37Z |
| format | Article |
| id | doaj.art-b5899ca3935e4b179f663e1e67cf8d05 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-11T04:06:37Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-b5899ca3935e4b179f663e1e67cf8d052023-01-01T12:21:12ZengBMCBMC Medicine1741-70152022-12-0120112510.1186/s12916-022-02699-1Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disordersP. Auvinen0J. Vehviläinen1H. Marjonen2V. Modhukur3J. Sokka4E. Wallén5K. Rämö6L. Ahola7A. Salumets8T. Otonkoski9H. Skottman10M. Ollikainen11R. Trokovic12H. Kahila13N. Kaminen-Ahola14Environmental Epigenetics Laboratory, Department of Medical and Clinical Genetics, Medicum, University of HelsinkiEnvironmental Epigenetics Laboratory, Department of Medical and Clinical Genetics, Medicum, University of HelsinkiEnvironmental Epigenetics Laboratory, Department of Medical and Clinical Genetics, Medicum, University of HelsinkiDepartment of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of TartuResearch Programs Unit, Stem cells and Metabolism and Biomedicum Stem Cell Centre, Faculty of Medicine, University of HelsinkiEnvironmental Epigenetics Laboratory, Department of Medical and Clinical Genetics, Medicum, University of HelsinkiEnvironmental Epigenetics Laboratory, Department of Medical and Clinical Genetics, Medicum, University of HelsinkiEnvironmental Epigenetics Laboratory, Department of Medical and Clinical Genetics, Medicum, University of HelsinkiDepartment of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of TartuResearch Programs Unit, Stem cells and Metabolism and Biomedicum Stem Cell Centre, Faculty of Medicine, University of HelsinkiFaculty of Medicine and Health Technology, Tampere UniversityInstitute for Molecular Medicine, Finland, FIMM, HiLIFE, University of HelsinkiResearch Programs Unit, Stem cells and Metabolism and Biomedicum Stem Cell Centre, Faculty of Medicine, University of HelsinkiObstetrics and Gynecology, Helsinki University Hospital, University of HelsinkiEnvironmental Epigenetics Laboratory, Department of Medical and Clinical Genetics, Medicum, University of HelsinkiAbstract Background Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neuronal disorders and birth defects. We hypothesize that early alcohol-induced epigenetic changes disrupt the accurate developmental programming of embryo and consequently cause the complex phenotype of developmental disorders. To explore the etiology of FASD, we collected unique biological samples of 80 severely alcohol-exposed and 100 control newborns at birth. Methods We performed genome-wide DNA methylation (DNAm) and gene expression analyses of placentas by using microarrays (EPIC, Illumina) and mRNA sequencing, respectively. To test the manifestation of observed PAE-associated DNAm changes in embryonic tissues as well as potential biomarkers for PAE, we examined if the changes can be detected also in white blood cells or buccal epithelial cells of the same newborns by EpiTYPER. To explore the early effects of alcohol on extraembryonic placental tissue, we selected 27 newborns whose mothers had consumed alcohol up to gestational week 7 at maximum to the separate analyses. Furthermore, to explore the effects of early alcohol exposure on embryonic cells, human embryonic stem cells (hESCs) as well as hESCs during differentiation into endodermal, mesodermal, and ectodermal cells were exposed to alcohol in vitro. Results DPPA4, FOXP2, and TACR3 with significantly decreased DNAm were discovered—particularly the regulatory region of DPPA4 in the early alcohol-exposed placentas. When hESCs were exposed to alcohol in vitro, significantly altered regulation of DPPA2, a closely linked heterodimer of DPPA4, was observed. While the regulatory region of DPPA4 was unmethylated in both control and alcohol-exposed hESCs, alcohol-induced decreased DNAm similar to placenta was seen in in vitro differentiated mesodermal and ectodermal cells. Furthermore, common genes with alcohol-associated DNAm changes in placenta and hESCs were linked exclusively to the neurodevelopmental pathways in the enrichment analysis, which emphasizes the value of placental tissue when analyzing the effects of prenatal environment on human development. Conclusions Our study shows the effects of early alcohol exposure on human embryonic and extraembryonic cells, introduces candidate genes for alcohol-induced developmental disorders, and reveals potential biomarkers for prenatal alcohol exposure.https://doi.org/10.1186/s12916-022-02699-1Prenatal alcohol exposurePAEFASDDNA methylationGene expressionPlacenta |
| spellingShingle | P. Auvinen J. Vehviläinen H. Marjonen V. Modhukur J. Sokka E. Wallén K. Rämö L. Ahola A. Salumets T. Otonkoski H. Skottman M. Ollikainen R. Trokovic H. Kahila N. Kaminen-Ahola Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders BMC Medicine Prenatal alcohol exposure PAE FASD DNA methylation Gene expression Placenta |
| title | Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders |
| title_full | Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders |
| title_fullStr | Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders |
| title_full_unstemmed | Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders |
| title_short | Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders |
| title_sort | chromatin modifier developmental pluripotency associated factor 4 dppa4 is a candidate gene for alcohol induced developmental disorders |
| topic | Prenatal alcohol exposure PAE FASD DNA methylation Gene expression Placenta |
| url | https://doi.org/10.1186/s12916-022-02699-1 |
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