Parenti Mariana, Melough Melissa M, Lapehn Samantha, MacDonald James, Bammler Theo, Firsick Evan J, Choi Hyo Young, Derefinko Karen J, Enquobahrie Daniel A, Carroll Kecia N, LeWinn Kaja Z, Bush Nicole R, Zhao Qi, Sathyanarayana Sheela, Paquette Alison G
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, United States.
Department of Health Behavior and Nutrition Sciences, University of Delaware, Newark, DE, United States.
bioRxiv. 2024 May 12:2024.05.10.593571. doi: 10.1101/2024.05.10.593571.
Vitamin D is a hormone regulating gene transcription. Prenatal vitamin D has been linked to immune and vascular function in the placenta, a key organ of pregnancy. To date, studies of vitamin D and placental gene expression have focused on a limited number of candidate genes. Transcriptome-wide RNA sequencing can provide a more complete representation of the placental effects of vitamin D.
We investigated the association between prenatal vitamin D levels and placental gene expression in a large, prospective pregnancy cohort.
Participants were recruited in Shelby County, Tennessee in the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study. Vitamin D level (plasma total 25-hydroxyvitatmin D, [25(OH)D]) was measured at mid-pregnancy (16-28 weeks' gestation) and delivery. Placenta samples were collected at birth. RNA was isolated and sequenced. We identified differentially expressed genes (DEGs) using adjusted linear regression models. We also conducted weighted gene co-expression network analysis (WGCNA).
The median 25(OH)D of participants was 21.8 ng/mL at mid-pregnancy (=774, IQR: 15.4-26.5 ng/mL) and 23.6 ng/mL at delivery (=753, IQR: 16.8-29.1 ng/mL). Placental expression of 25 DEGs was associated with 25(OH)D at mid-pregnancy, but no DEG was associated with 25(OH)D at delivery. DEGs were related to energy metabolism, cytoskeletal function, and RNA transcription. Using WGCNA, we identified 2 gene modules whose expression was associated with 25(OH)D at mid-pregnancy and 1 module associated with 25(OH)D at delivery. These modules were enriched for genes related to mitochondrial and cytoskeletal function, and were regulated by transcription factors including , , , , and .
Our results indicate that 25(OH)D during mid-pregnancy, but not at delivery, is associated with placental gene expression at birth. Future research is needed to investigate a potential role of vitamin D in programming placental mitochondrial metabolism, intracellular transport, and transcriptional regulation during pregnancy.
维生素D是一种调节基因转录的激素。孕期维生素D与胎盘（妊娠的关键器官）的免疫和血管功能有关。迄今为止，关于维生素D与胎盘基因表达的研究主要集中在少数候选基因上。全转录组RNA测序能够更全面地呈现维生素D对胎盘的影响。
我们在一个大型前瞻性妊娠队列中研究了孕期维生素D水平与胎盘基因表达之间的关联。
在田纳西州谢尔比县的影响儿童早期神经认知发育和学习状况（CANDLE）研究中招募参与者。在妊娠中期（妊娠16 - 28周）和分娩时测量维生素D水平（血浆总25 - 羟基维生素D，[25(OH)D]）。出生时采集胎盘样本。分离RNA并进行测序。我们使用调整后的线性回归模型鉴定差异表达基因（DEGs）。我们还进行了加权基因共表达网络分析（WGCNA）。
参与者妊娠中期的25(OH)D中位数为21.8 ng/mL（n = 774，四分位间距：15.4 - 26.5 ng/mL），分娩时为23.6 ng/mL（n = 753，四分位间距：16.8 - 29.1 ng/mL）。25个差异表达基因的胎盘表达与妊娠中期的25(OH)D相关，但没有差异表达基因与分娩时的25(OH)D相关。差异表达基因与能量代谢、细胞骨架功能和RNA转录有关。使用WGCNA，我们鉴定出2个基因模块，其表达与妊娠中期的25(OH)D相关，1个模块与分娩时的25(OH)D相关。这些模块富含与线粒体和细胞骨架功能相关的基因，并受包括……、……、……、……和……在内的转录因子调控。
我们的结果表明，妊娠中期而非分娩时的25(OH)D与出生时的胎盘基因表达相关。未来需要开展研究，以探究维生素D在孕期胎盘线粒体代谢、细胞内运输和转录调控编程中的潜在作用。
