Abstract
<jats:p>Background: Prenatal growth restriction has been associated with adverse neonatal and long-term health outcomes, yet the epigenetic mechanisms by which an adverse intrauterine environment shapes fetal immune development remain incompletely understood. Monozygotic dichorionic-diamniotic twins with selective fetal growth restriction (sFGR) provide a unique human model for investigating environmentally driven developmental programming independent of genetic variation and inter-twin placental vascular anastomoses. Methods: Umbilical cord blood buffy coat samples were collected from three sFGR and two gestational age-matched concordant control twin pairs. Bulk RNA sequencing and genome-wide DNA methylation analysis were performed, followed by differential expression, pathway enrichment, hematopoietic and immune module analyses, differential methylation, and integrative transcriptomic-epigenomic analyses. Results: Compared with concordant control twin pairs, discordant twins exhibited broad attenuation of immune and inflammatory transcriptional programs alongside enrichment of erythroid- and hypoxia-related pathways, consistent with adaptive hematopoietic responses to intrauterine stress. Within discordant twin pairs, the growth-restricted co-twins displayed marked transcriptional asymmetry characterized by selective enrichment of cytotoxic lymphoid signatures despite global suppression of myeloid and antigen-presenting cell-associated programs. Integrated transcriptomic and epigenomic analyses further revealed coordinated epigenetic remodeling, with hypomethylated regions in growth-restricted twins enriched for immune regulatory pathways, including T cell differentiation and leukocyte activation. At selected loci, concordant hypomethylation and increased gene expression suggested a potential epigenetic basis for the observed immune remodeling. Conclusions: These findings suggest that intrauterine growth restriction is associated with coordinated hematopoietic and immune reprogramming at birth, consistent with both compositional and cell-intrinsic alterations. In genetically identical twins, relative growth divergence was associated with polarized transcriptional states, highlighting how intrauterine environmental differences may shape early immune development independent of genetic background.</jats:p>