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. 2018 Mar 28;10(4):417.
doi: 10.3390/nu10040417.

Maternal Choline Supplementation during Normal Murine Pregnancy Alters the Placental Epigenome: Results of an Exploratory Study

Sze Ting Cecilia Kwan  1 , Julia H King  2 , Jennifer K Grenier  3 , Jian Yan  4 , Xinyin Jiang  5   6 , Mark S Roberson  7 , Marie A Caudill  8
Affiliations

Maternal Choline Supplementation during Normal Murine Pregnancy Alters the Placental Epigenome: Results of an Exploratory Study

Sze Ting Cecilia Kwan et al. Nutrients. .

Abstract

The placental epigenome regulates processes that affect placental and fetal development, and could be mediating some of the reported effects of maternal choline supplementation (MCS) on placental vascular development and nutrient delivery. As an extension of work previously conducted in pregnant mice, the current study sought to explore the effects of MCS on various epigenetic markers in the placenta. RNA and DNA were extracted from placentas collected on embryonic day 15.5 from pregnant mice fed a 1X or 4X choline diet, and were subjected to genome-wide sequencing procedures or mass-spectrometry-based assays to examine placental imprinted gene expression, DNA methylation patterns, and microRNA (miRNA) abundance. MCS yielded a higher (fold change = 1.63-2.25) expression of four imprinted genes (Ampd3, Tfpi2, Gatm and Aqp1) in the female placentas and a lower (fold change = 0.46-0.62) expression of three imprinted genes (Dcn, Qpct and Tnfrsf23) in the male placentas (false discovery rate (FDR) ≤ 0.05 for both sexes). Methylation in the promoter regions of these genes and global placental DNA methylation were also affected (p ≤ 0.05). Additionally, a lower (fold change = 0.3; Punadjusted = 2.05 × 10-4; FDR = 0.13) abundance of miR-2137 and a higher (fold change = 1.25-3.92; p < 0.05) expression of its target genes were detected in the 4X choline placentas. These data demonstrate that the placental epigenome is responsive to maternal choline intake during murine pregnancy and likely mediates some of the previously described choline-induced effects on placental and fetal outcomes.

Keywords: DNA methylation; choline; imprinted genes; microRNA; placenta.

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Conflict of interest statement

The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Average percentage of cytosine-phosphate-guanine (CpG) methylation across the promoter region and the percentage of methylation of each CpG unit within the promoter region of (A) Aqp1; (B) Tfpi2; (C) Ampd3; and (D) Gatm in the female placentas from dams in the 1X and 4X choline groups. Each CpG unit may contain more than one CpG site. Only CpG units with measurements that met the quality control criteria were included in the final analyses. One placenta (either male or female) from each dam (n = 3 dams per treatment, per fetal sex) was used, and each placenta was considered to be a statistical unit in the statistical analysis. Data were analyzed using one-way ANOVA and are presented as means with 95% confidence intervals. * p ≤ 0.05.
Figure 1
Figure 1
Average percentage of cytosine-phosphate-guanine (CpG) methylation across the promoter region and the percentage of methylation of each CpG unit within the promoter region of (A) Aqp1; (B) Tfpi2; (C) Ampd3; and (D) Gatm in the female placentas from dams in the 1X and 4X choline groups. Each CpG unit may contain more than one CpG site. Only CpG units with measurements that met the quality control criteria were included in the final analyses. One placenta (either male or female) from each dam (n = 3 dams per treatment, per fetal sex) was used, and each placenta was considered to be a statistical unit in the statistical analysis. Data were analyzed using one-way ANOVA and are presented as means with 95% confidence intervals. * p ≤ 0.05.
Figure 2
Figure 2
Average percentage of cytosine-phosphate-guanine (CpG) methylation across the promoter region and percentage of methylation of each CpG unit within the promoter regions of (A) Qpct; (B) Dcn and (C) Tnfrsf23 in male placentas from dams in the 1X and 4X choline groups. Each CpG unit may contain more than one CpG site. Only CpG units with measurements that met the quality control criteria were included in the final analyses. One placenta (either male or female) from each dam (n = 3 dams per treatment, per fetal sex) was used, and each placenta was considered to be a statistical unit in the statistical analysis. Data were analyzed using one-way ANOVA and are presented as means with 95% confidence intervals. * p ≤ 0.05. # 0.05 < p < 0.1.
Figure 3
Figure 3
Percentage of global DNA methylation in the placentas from dams in the 1X and 4X choline groups. One placenta (either male or female) from each dam (n = 3 dams per treatment, per fetal sex) was used, and each placenta was considered to be a statistical unit in the statistical analysis. Data were first analyzed without stratification by fetal sex and then separately for each fetal sex using one-way ANOVA. Results are presented as means with 95% confidence intervals. * p ≤ 0.05. # p = 0.086.
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