Prematurity and Epigenetic Regulation of SLC6A4: Longitudinal Insights from Birth to the First Month of Life

TL;DR

This study shows that preterm infants have distinct DNA methylation patterns in the SLC6A4 gene compared to full-term infants, which may affect their neurodevelopment and stress adaptation.

Contribution

The study provides longitudinal insights into SLC6A4 methylation differences in preterm and term neonates, linking epigenetic regulation to early-life stress and neurodevelopment.

Findings

Preterm infants showed higher methylation at CpGs 12 and 13 at birth compared to full-term infants.

Methylation patterns in preterm infants remained stable over time, while full-term infants showed increasing methylation at certain CpG sites.

Extremely preterm infants exhibited the highest methylation levels across all three time points.

Abstract

Background/Objectives: Prematurity is a significant global health concern, often associated with neurodevelopmental challenges. Solute Carrier Family 6 Member 4 (SLC6A4), the gene encoding the serotonin transporter, a key component in serotonin reuptake in the synaptic cleft, plays a key role in stress response and neurodevelopment. Epigenetic regulation of stress-related genes, such as SLC6A4, influences neonatal stress adaptation and developmental outcomes. This study aimed to quantify and compare DNA methylation levels at 13 CpG sites in the promoter region of the SLC6A4 gene between preterm and term neonates at three time points. Methods: A cohort of 46 preterm infants and a cohort of 49 full-term infants were analyzed. Blood samples collected at birth (D0), the fifth day (D5), and the thirtieth day (D30) were used to analyze DNA methylation, using bisulfite conversion and pyrosequencing. Results: Significant differences in SLC6A4 methylation were observed. At D0, CpGs 12 and 13 showed higher methylation in preterm infants. CpG 9 showed lower methylation in preterm infants at D5. Extremely preterm infants had the highest values of methylation at the three time points. Longitudinal mixed-effects analysis revealed distinct temporal patterns between groups. Total and site-specific methylation at CpGs 2, 8, and 9 increased over time in full-term infants, while methylation remained stable over time in very preterm and extremely preterm infants. Conclusions: This study reveals significant differences in SLC6A4 methylation between very preterm, extremely preterm, and full-term infants, highlighting the impact of prematurity and early-life stress on the epigenome. These findings contribute to improving our understanding of the epigenetic mechanisms shaping neurodevelopment and stress adaptation in neonates.

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