ESPE Abstracts (2015) 84 P-2-470

Hypomethylation within the Imprinted Dlk1 - Dio3 Domain: a Potential Regulatory Mechanism of Pre and Postnatal Growth

Anna Prats-Puiga,c, Gemma Carreras-Badosaa,b, Judit Bassolsa,b, Patricia Cavelierf, Agnés Magretb, Cristina Sabenchb, Francis de Zegherd, Lourdes Ibáñeze, Robert Feilf & Abel López-Bermejoa,b

aGirona Institute for Biomedical Research, Girona, Spain; bDr. JosepTrueta Hospital, Girona, Spain; cEUSES University School, Girona, Spain; dUniversity of Leuven, Leuven, Belgium; eHospital Sant Joan de Déu, Barcelona, Spain; fInstitut de Génétique Moléculaire de Montpellier, Montpellier, France

Background: Genomic imprinting causes genes to be expressed or repressed depending on their parental origin. The 1-Mb DLK1-DIO3 imprinted domain is located on human chromosome 14. Gene expression along this cluster is regulated by an intergenic differentially methylated imprinting control region (‘IG-DMR’). In mice, altered gene dosage within this cluster is associated with alterations in embryonic and placental growth.

Objective and hypotheses: To study the association between DLK1-DIO3 IG-DMR methylation and placental, foetal and postnatal growth in humans.

Method: We studied by means of pyrosequencing the DNA methylation of 18 CpG dinucleotides across the IG-DMR in placentae from 80 healthy mothers who delivered healthy infants. The studied chromosomal locations within the cluster were: Region 1: chr14:101270990-101271064; Region 2: chr14:101278037-101278081 and Region 3: chr14:101292465-101292596. At birth, placentas and infants were weighed (gestational age 39±1 weeks; birth weight Z-score 0.31±0.89) and placenta samples were collected. Infants’ weights were measured monthly during the first year of life.

Results: Children with hypomethylation within region 3 showed lower birth weight-to-placental weight ratios (r=0.316; P=0.014) and higher increases in weight during the first year of life (r=−0.380; P=0.004). We also performed analyses of individual CpG sites within region 1 and 2. In region 1, lower levels of methylation were related to lower birth weight (r=0.270; 0.017) while two different CpGs in region 2 showed significant associations, respectively, with placental weight (position 1: r=−0.306; P=0.011) and weight increase during the first year of life (position 5; r=−0.301; 0.044). All these associations remained significant after adjusting for confounding variables.

Conclusion: For the first time, we show that placental hypomethylation at the DLK1-DIO3 IG-DMR is associated with decreased foetal growth and increased placental weight and postnatal growth. We suggest that hypomethylation in the DLK1-DIO3 imprinted domain may be a new mechanism regulating pre and postnatal growth in humans.

Funding: This study was supported by a grant from the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (ISCIII), Madrid, Spain (PI13/01257), project co-financed by FEDER.