Gestational trophoblastic diseases (GTDs) have not been investigated for their epigenetic
marks and consequent transcriptomic changes. Here, we analyzed genome-wide DNA methylation
and transcriptome data to reveal the epigenetic basis of disease pathways that may
lead to benign or malignant GTDs. RNA-Seq, mRNA microarray, and Human Methylation
450 BeadChip data from complete moles and choriocarcinoma cells were bioinformatically
analyzed. Paraffin-embedded tissues from complete moles and control placentas were
used for tissue microarray construction, DNMT3B immunostaining and immunoscoring.
We found that DNA methylation increases with disease severity in GTDs. Differentially
expressed genes are mainly upregulated in moles while predominantly downregulated
in choriocarcinoma. DNA methylation principally influences the gene expression of
villous trophoblast differentiation-related or predominantly placenta-expressed genes
in moles and choriocarcinoma cells. Affected genes in these subsets shared focal adhesion
and actin cytoskeleton pathways in moles and choriocarcinoma. In moles, cell cycle
and differentiation regulatory pathways, essential for trophoblast/placental development,
were enriched. In choriocarcinoma cells, hormone biosynthetic, extracellular matrix-related,
hypoxic gene regulatory, and differentiation-related signaling pathways were enriched.
In moles, we found slight upregulation of DNMT3B protein, a developmentally important
de novo DNA methylase, which is strongly overexpressed in choriocarcinoma cells that
may partly be responsible for the large DNA methylation differences. Our findings
provide new insights into the shared and disparate molecular pathways of disease in
GTDs and may help in designing new diagnostic and therapeutic tools.
