Early maternal care restores LINE-1 methylation and enhances neurodevelopment in preterm infants.

Affiliation

Fontana C(#)(1), Marasca F(#)(2), Provitera L(3), Mancinelli S(4)(5), Pesenti N(3)(6), Sinha S(2), Passera S(3), Abrignani S(1)(2), Mosca F(1)(3), Lodato S(4)(5), Bodega B(#)(7), Fumagalli M(#)(8)(9).
Author information:
(1)Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
(2)Istituto Nazionale di Genetica Molecolare "Enrica e Romeo Invernizzi"
(INGM), Milan, Italy.
(3)Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, NICU, Milan, Italy.
(4)Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
(5)IRCCS Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
(6)Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca, Milan, Italy.
(7)Istituto Nazionale di Genetica Molecolare "Enrica e Romeo Invernizzi"
(INGM), Milan, Italy. [Email]
(8)Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. [Email]
(9)Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, NICU, Milan, Italy. [Email]
(#)Contributed equally

Abstract

BACKGROUND: Preterm birth affects almost 9-11% of newborns and is one of the leading causes of childhood neurodevelopmental disabilities; the underlying molecular networks are poorly defined. In neurons, retrotransposons LINE-1 (L1) are an active source of genomic mosaicism that is deregulated in several neurological disorders; early life experience has been shown to regulate L1 activity in mice. 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 and 36 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: Here we report that L1 promoter is hypomethylated in preterm infants at birth and that an early intervention program, based on enhanced maternal care and positive multisensory stimulation, restores L1 methylation levels comparable to healthy newborns and ameliorates neurodevelopment in childhood. We further show that L1 activity is fine-tuned in the perinatal mouse brain, suggesting a sensitive and vulnerable window for the L1 epigenetic setting. CONCLUSIONS: Our results open the field on the inspection of L1 activity as a novel molecular and predictive approach to infants' prematurity-related neurodevelopmental outcomes. TRIAL REGISTRATION: ClinicalTrial.gov ( NCT02983513 ). Registered on 6 December 2016, retrospectively registered.