DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases.
3',5'-Cyclic-AMP Phosphodiesterases
/ genetics
Adult
Birth Weight
/ genetics
Cardiometabolic Risk Factors
CpG Islands
/ genetics
DNA Methylation
/ genetics
Diabetes Mellitus, Type 2
/ genetics
Epigenesis, Genetic
/ genetics
Female
Fetal Blood
/ metabolism
Fetal Development
/ genetics
GTPase-Activating Proteins
/ genetics
Gene Expression
/ genetics
Humans
Infant, Low Birth Weight
/ metabolism
Infant, Newborn
Maternal-Fetal Exchange
/ genetics
Neoplasm Proteins
/ genetics
Nuclear Proteins
/ genetics
Placenta
/ metabolism
Pre-Eclampsia
/ genetics
Pregnancy
/ ethnology
Proto-Oncogene Proteins c-fos
/ genetics
Sodium-Phosphate Cotransporter Proteins, Type III
/ genetics
Transcription Factors
/ genetics
Birthweight
DNA methylation
Developmental origins of health and disease (DOHaD)
Expression quantitative trait methylation (eQTM)
Fetal growth
Placenta
Transcriptomics
Journal
Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977
Informations de publication
Date de publication:
03 06 2020
03 06 2020
Historique:
received:
05
02
2020
accepted:
21
05
2020
entrez:
5
6
2020
pubmed:
5
6
2020
medline:
19
8
2021
Statut:
epublish
Résumé
Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life. We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta. We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases. ClinicalTrials.gov, NCT00912132.
Sections du résumé
BACKGROUND
Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life.
RESULTS
We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta.
CONCLUSION
We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT00912132.
Identifiants
pubmed: 32493484
doi: 10.1186/s13148-020-00873-x
pii: 10.1186/s13148-020-00873-x
pmc: PMC7268466
doi:
Substances chimiques
GTPase-Activating Proteins
0
MLLT1 protein, human
0
Neoplasm Proteins
0
Nuclear Proteins
0
Proto-Oncogene Proteins c-fos
0
SLC20A2 protein, human
0
Sodium-Phosphate Cotransporter Proteins, Type III
0
Transcription Factors
0
fos-related antigen 1
0
3',5'-Cyclic-AMP Phosphodiesterases
EC 3.1.4.17
PDE9A protein, human
EC 3.1.4.17
ASAP2 protein, human
EC 3.6.1.-
Banques de données
ClinicalTrials.gov
['NCT00912132']
Types de publication
Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
78Subventions
Organisme : NICHD NIH HHS
ID : HHSN275200800013C
Pays : United States
Organisme : NICHD NIH HHS
ID : HHSN275200800002I
Pays : United States
Organisme : NICHD NIH HHS
ID : HHSN275200800014C
Pays : United States
Organisme : NICHD NIH HHS
ID : HHSN275200800012C
Pays : United States
Organisme : NICHD NIH HHS
ID : HHSN275200800028C
Pays : United States
Organisme : NICHD NIH HHS
ID : HHSN275201000009C
Pays : United States
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