Epigenetics and Preeclampsia: Defining Functional Epimutations in the Preeclamptic Placenta Related to the TGF-β Pathway.
Preeclampsia is a potentially fatal pregnancy disorder affecting millions of women around the globe. Dysregulation in gene and protein expression within key biological pathways controlling angiogenesis has been implicated in the development of preeclampsia. Altered CpG methylation, a type of epimutation, may underlie this pathway dysregulation. In the present study, placental tissue from preeclamptic cases and normotensive controls was analyzed for genome-wide differential CpG methylation and concomitant changes in gene expression. A set of 123 genes, representing 19.9% of all genes with altered CpG methylation, was associated with functional changes in transcript levels. Underscoring the complex relationships between CpG methylation and gene expression, here hypermethylation was never associated with gene silencing, nor was hypomethylation always associated with gene activation. Moreover, the genomic region of the CpG mark was important in predicting the relationship between CpG methylation and gene expression. The 123 genes were enriched for their involvement in the transforming growth factor beta (TGF-β) signaling pathway, a known regulator of placental trophoblast invasion and migration. This is the first study to identify CpG hypomethylation as an activator of TGF-β-associated gene expression in the preeclamptic placenta. The results suggest functional epimutations are associated with preeclampsia disease status and the identified genes may represent novel biomarkers of disease.
Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, 135 Dauer Drive, CB 7431, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Elizabeth
E
Martin
Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, 135 Dauer Drive, CB 7431, University of North Carolina, Chapel Hill, North Carolina, United States of America; Curriculum in Toxicology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Paul D
PD
Ray
Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, 135 Dauer Drive, CB 7431, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Lisa
L
Smeester
Department of Obstetrics & Gynecology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Matthew R
MR
Grace
Department of Obstetrics & Gynecology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Kim
K
Boggess
Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, 135 Dauer Drive, CB 7431, University of North Carolina, Chapel Hill, North Carolina, United States of America; Curriculum in Toxicology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Rebecca C
RC
Fry
D000328:Adult; D016022:Case-Control Studies; D016000:Cluster Analysis; D015331:Cohort Studies; D019295:Computational Biology; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005865:Gestational Age; D006801:Humans; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism*; D011247:Pregnancy; D060066:Protein Interaction Maps; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016212:Transforming Growth Factor beta