Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseases

Fasil Tekola-Ayele (), Richard J. Biedrzycki, Tesfa Dejenie Habtewold, Prabhavi Wijesiriwardhana, Amber Burt, Carmen J. Marsit, Marion Ouidir and Ronald Wapner
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Fasil Tekola-Ayele: National Institutes of Health
Richard J. Biedrzycki: National Institutes of Health
Tesfa Dejenie Habtewold: National Institutes of Health
Prabhavi Wijesiriwardhana: National Institutes of Health
Amber Burt: Rollins School of Public Health of Emory University
Carmen J. Marsit: Rollins School of Public Health of Emory University
Marion Ouidir: National Institutes of Health
Ronald Wapner: Columbia University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58128-3

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