Early Intervention in preterm infants modulates LINE-1 promoter methylation and neurodevelopment

Background: Early life adversity exposure impacts preterm infants neurodevelopment and early intervention protocols may modulate neurodevelopmental outcomes. Neuronal genomes are plastic in response to environment and mobile genetic elements, including LINE-1 (L1), are source of brain genomic mosaicism. Maternal care during early life regulates L1 methylation and copy number variations (CNVs) in mice. Here, we sought to identify the effects of maternal care and positive multisensory stimulation (Early Intervention) on L1 methylation and neurodevelopment in preterm infants. Methods: Very preterm infants were randomized to receive Standard Care or Early Intervention. L1 methylation was measured at birth and at hospital discharge. At 12 months infants neurodevelopment was evaluated with the Griffiths Scales. L1 methylation and CNVs were measured in mouse brain areas at embryonic and postnatal stages. Results: We demonstrated that L1 is hypomethylated in preterm versus term infants at birth. Early Intervention contributes to restore L1 methylation and positively modulates neurodevelopment. We showed that L1 methylation is developmentally-regulated in mice, decreasing in early postnatal life stages, which turns into an increased L1 CNVs specifically in hippocampus and cortex. Conclusions: Here we demonstrated that L1 dynamics can be modulated by Early Intervention, in parallel with ameliorated neurodevelopmental outcomes. We further identified a specific developmental window of the fetal mouse brain, sensitive to early life experience, in which L1 dynamics are fine-tuned contributing to shape the brain genomic landscape.