DNA methylation and expression profiles of placenta and umbilical cord blood reveal the characteristics of gestational diabetes mellitus patients and offspring

Abstract

Background Gestational diabetes mellitus (GDM) is a common pregnancy-specific disease and is growing at an alarming rate worldwide, which can negatively affect the health of pregnant women and fetuses. However, most studies are limited to one tissue, placenta or umbilical cord blood, usually with one omics assay. It is thus difficult to systematically reveal the molecular mechanism of GDM and the key influencing factors on pregnant women and offspring. Results We recruited a group of 21 pregnant women with GDM and 20 controls without GDM. For each pregnant woman, reduced representation bisulfite sequencing and RNA-seq were performed using the placenta and paired neonatal umbilical cord blood specimens. Differentially methylated regions (DMRs) and differentially expressed genes (DEGs) were identified with body mass index as a covariate. Through the comparison of GDM and control samples, 2779 and 141 DMRs, 1442 and 488 DEGs were identified from placenta and umbilical cord blood, respectively. Functional enrichment analysis showed that the placenta methylation and expression profiles of GDM women mirrored the molecular characteristics of “type II diabetes” and “insulin resistance.” Methylation-altered genes in umbilical cord blood were associated with pathways “type II diabetes” and “cholesterol metabolism.” Remarkably, both DMRs and DEGs illustrated significant overlaps among placenta and umbilical cord blood samples. The overlapping DMRs were associated with “cholesterol metabolism.” The top-ranking pathways enriched in the shared DEGs include “growth hormone synthesis, secretion and action” and “type II diabetes mellitus.” Conclusions Our research demonstrated the epigenetic and transcriptomic alternations of GDM women and offspring. Our findings emphasized the importance of epigenetic modifications in the communication between pregnant women with GDM and offspring, and provided a reference for the prevention, control, treatment, and intervention of perinatal deleterious events of GDM and neonatal complications.

Placental DNA methylation in pregnancies complicated by maternal diabetes and/or obesity: State of the art and research gaps

“…Pathway analysis found DNAm changes related to T2D and insulin resistance pathways. No data on foetal sex Lu et al, 2022 [ 88 ] 80 GDM 119 Ctrl PS HTR2A Increased pre-pregnancy BMI and GDM was independently associated with lower promoter DNAm in female but not male placentas. Stratified for foetal sex Horvatiček et al, 2022 [ 89 ] 34 GDM 46 Ctrl PS LEP Higher DNAm in placenta from women with GDM of South Asian ethnicity but not European ethnicity.…”

Gestational diabetes mellitus changes the DNA methylation profile in cord blood and leads to neonatal immune dysregulation

“…Umbilical cord blood testing monitors the fetus's health during development in the clinical setting [25]. However, detecting DNA methylation in the cord blood of GDM pregnant women is not ideal [17,22]. To improve this situation, this study reduced the in uence of other characteristics on the results at the sample collection level.…”

“…To reduce the in uence of other characteristics on the results, in this study, we recruited pregnant women at the sample collection level with no signi cant differences in other attributes except OGTT characteristics. If there are other features, covariance correction will be carried out [17], but the data obtained by covariance correction are not actual data. For the correctness of the data, it is suggested that the test samples should be strictly screened.…”

“…Most CpG sites are located near the promoter region, but some CpG sites also exist in exons, introns, enhancers and other positions of genes [16]. For example, the DMRs of the TFAP2A gene and DAB2IP gene is located in the downstream and intron regions, respectively, but the gene expression has changed signi cantly [17]. Of course, in addition to DNA methylation affecting gene expression, other factors also regulate gene expression.…”

Predictive Gestational Diabetes Biomarkers With Sustained Alterations Throughout Pregnancy

“…Elevated phosphatidic acid may play a role in mTORC1 signaling, thereby contributing to insulin resistance [ 110 , 112 ], while betaine is important for methylation via the action of betaine-homocysteine S-methyltransferase [ 111 ]. Dysregulated phospholipase D signaling, and hypermethylation that alters genomic regions related to insulin resistance, has been observed in GDM [ 113 ]. Furthermore, elevated betaine-homocysteine S-methyltransferase mRNA has been observed in diabetic rats [ 111 ], suggesting the involvement of betaine in insulin resistance development via alterations in methylation, though further research is necessary to fully understand this connection.…”