Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseases
Abstract Sex differences in physiological and disease traits are pervasive and begin during early development, but the genetic architecture of these differences is largely unknown. Here, we leverage the human placenta, a transient organ during pregnancy critical to fetal development, to investigate...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58128-3 |
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| author | Fasil Tekola-Ayele Richard J. Biedrzycki Tesfa Dejenie Habtewold Prabhavi Wijesiriwardhana Amber Burt Carmen J. Marsit Marion Ouidir Ronald Wapner |
| author_facet | Fasil Tekola-Ayele Richard J. Biedrzycki Tesfa Dejenie Habtewold Prabhavi Wijesiriwardhana Amber Burt Carmen J. Marsit Marion Ouidir Ronald Wapner |
| author_sort | Fasil Tekola-Ayele |
| collection | DOAJ |
| description | Abstract Sex differences in physiological and disease traits are pervasive and begin during early development, but the genetic architecture of these differences is largely unknown. Here, we leverage the human placenta, a transient organ during pregnancy critical to fetal development, to investigate the impact of sex in the regulatory landscape of placental autosomal methylome and transcriptome, and its relevance to health and disease. We find that placental methylation and its genetic regulation are extensively impacted by fetal sex, whereas sex differences in placental gene expression and its genetic regulation are limited. We identify molecular processes and regulatory targets that are enriched in a sex-specific manner, and find enrichment of imprinted genes in sex-differentiated placental methylation, including female-biased methylation within the well-known KCNQ1OT1/CDKN1C imprinting cluster of genes expressed in a parent-of-origin dependent manner. We establish that several sex-differentiated genetic effects on placental methylation and gene expression colocalize with birthweight and adult disease genetic associations, facilitating mechanistic insights on early life origins of health and disease outcomes shaped by sex. |
| format | Article |
| id | doaj-art-5bd9f3a1260a4585bd4c4e5f7faaf348 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5bd9f3a1260a4585bd4c4e5f7faaf3482025-08-20T01:47:32ZengNature PortfolioNature Communications2041-17232025-05-0116111910.1038/s41467-025-58128-3Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseasesFasil Tekola-Ayele0Richard J. Biedrzycki1Tesfa Dejenie Habtewold2Prabhavi Wijesiriwardhana3Amber Burt4Carmen J. Marsit5Marion Ouidir6Ronald Wapner7Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthGlotech, Inc., contractor for Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthDivision of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthDivision of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthGangarosa Department of Environmental Health, Rollins School of Public Health of Emory UniversityGangarosa Department of Environmental Health, Rollins School of Public Health of Emory UniversityDivision of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthDepartment of Obstetrics and Gynecology, Columbia UniversityAbstract Sex differences in physiological and disease traits are pervasive and begin during early development, but the genetic architecture of these differences is largely unknown. Here, we leverage the human placenta, a transient organ during pregnancy critical to fetal development, to investigate the impact of sex in the regulatory landscape of placental autosomal methylome and transcriptome, and its relevance to health and disease. We find that placental methylation and its genetic regulation are extensively impacted by fetal sex, whereas sex differences in placental gene expression and its genetic regulation are limited. We identify molecular processes and regulatory targets that are enriched in a sex-specific manner, and find enrichment of imprinted genes in sex-differentiated placental methylation, including female-biased methylation within the well-known KCNQ1OT1/CDKN1C imprinting cluster of genes expressed in a parent-of-origin dependent manner. We establish that several sex-differentiated genetic effects on placental methylation and gene expression colocalize with birthweight and adult disease genetic associations, facilitating mechanistic insights on early life origins of health and disease outcomes shaped by sex.https://doi.org/10.1038/s41467-025-58128-3 |
| spellingShingle | Fasil Tekola-Ayele Richard J. Biedrzycki Tesfa Dejenie Habtewold Prabhavi Wijesiriwardhana Amber Burt Carmen J. Marsit Marion Ouidir Ronald Wapner Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseases Nature Communications |
| title | Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseases |
| title_full | Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseases |
| title_fullStr | Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseases |
| title_full_unstemmed | Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseases |
| title_short | Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseases |
| title_sort | sex differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseases |
| url | https://doi.org/10.1038/s41467-025-58128-3 |
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