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. Trail Registration [clinicalTrial.gov][1] ([NCT02983513][2]) Funding Italian Ministry of Health (RC 780/03 2017), University of Milan (DISCCO 2015) and INGM internal funding. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT02983513 ### Funding Statement Italian Ministry of Health (RC 780/03 2017) and University of Milan (DISCCO 2015) and INGM internal funding. ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data available upon request. [1]: http://clinicalTrial.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02983513&atom=%2Fmedrxiv%2Fearly%2F2019%2F11%2F15%2F19011874.atom