Sex-influenced DNA methylation differs by placental cell type.

IF 5.3 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Biology of Sex Differences Pub Date : 2026-03-18 DOI:10.1186/s13293-026-00869-x

Jiyoung Han, Amy M Inkster, Victor Yuan, Maria S Peñaherrera, Wendy P Robinson

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引用次数: 0

Abstract

Background: Sex differences in the function and morphology of the human placenta can lead to sex differences in pregnancy outcomes. X chromosome inactivation (XCI) is the primary mechanism for dosage compensation between the sexes, and is strongly associated with X-chromosome promoter DNA methylation (DNAme) in somatic cells. However, in the placenta, low X-chromosome promoter DNAme has been reported. The placenta is a complex organ consisting of cells of different developmental origins, but the sex differences in DNAme by specific cell types have not been investigated.

Methods: We examined sex-influenced DNAme from 18 to 19 samples each of endothelial, stromal, cytotrophoblast and Hofbauer cells, sorted from term placentas, as well as matched whole chorionic villi. We also compared these profiles with data from 65 endothelial cell samples from placental chorionic plate arteries and veins (XX = 16, XY = 13) and umbilical cord veins (XX = 22, XY = 14). All data were derived from Illumina Infinium HumanMethylation450 or EPIC DNAme arrays. Sex-stratified analyses of the X/Y and autosomal DNAme were undertaken to identify DNAme differences associated with sex chromosome complement.

Results: The DNAme distribution on both the X and Y chromosomes differed by cell type. These differences clustered according to the differing developmental origins from extraembryonic mesoderm (endothelial/stromal), trophectoderm (cytotrophoblast) and epiblast (Hofbauer cells), with Hofbauer cells sharing a similar distribution with blood and umbilical endothelial cells. Interestingly, the typical XCI-associated DNAme at promoter CpG islands (CGI) on the X-chromosome of XX cells was absent for endothelial/stromal cells and present only at low levels in trophoblasts, suggesting that de novo establishment of promoter-CGI DNAme on the X-chromosome may differ by cell type.

Conclusion: The lack of X-linked promoter DNAme in extraembryonic mesoderm-derived cells (endothelial/stromal) is consistent with a distinct developmental origin of these populations relative to the other placental and umbilical cell types. Autosomal DNAme also showed cell-type differences in alignment with cellular relationships observed for sex chromosomes. This work suggests the effects of sex chromosome complement on pregnancy outcomes may differ by placental cell type.

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性别影响的DNA甲基化因胎盘细胞类型而异。

背景：人类胎盘功能和形态的性别差异可导致妊娠结局的性别差异。X染色体失活（XCI）是两性剂量补偿的主要机制，与体细胞中X染色体启动子DNA甲基化（DNAme）密切相关。然而，在胎盘中，低x染色体启动子DNAme已被报道。胎盘是一个由不同发育起源的细胞组成的复杂器官，但尚未研究特定细胞类型在DNAme上的性别差异。方法：从足月胎盘中分选的内皮细胞、间质细胞、细胞滋养细胞和霍夫鲍尔细胞，以及匹配的整个绒毛膜绒毛，分别检测18 ~ 19个样本的性别影响dna。我们还将这些数据与来自胎盘绒毛膜板动脉和静脉（XX = 16, XY = 13）和脐带静脉（XX = 22, XY = 14）的65个内皮细胞样本进行了比较。所有数据均来自Illumina Infinium HumanMethylation450或EPIC DNAme阵列。对X/Y和常染色体DNAme进行性别分层分析，以确定与性染色体补体相关的DNAme差异。结果：dna在X染色体和Y染色体上的分布随细胞类型的不同而不同。这些差异根据胚胎外中胚层（内皮细胞/间质细胞）、滋养外胚层（细胞滋养层）和外胚层（霍夫鲍尔细胞）的不同发育起源聚集在一起，霍夫鲍尔细胞与血液和脐带内皮细胞具有相似的分布。有趣的是，XX细胞x染色体上启动子CpG岛（CGI）上典型的xci相关DNAme在内皮/基质细胞中不存在，仅在滋养细胞中低水平存在，这表明启动子CGI DNAme在x染色体上的重新建立可能因细胞类型而异。结论：胚胎外中胚层来源的细胞（内皮细胞/间质细胞）缺乏x连锁启动子DNAme，这与这些群体相对于其他胎盘和脐带细胞类型的独特发育起源是一致的。常染色体DNAme也显示出与性染色体的细胞关系相符的细胞型差异。这项工作表明，性染色体补体对妊娠结局的影响可能因胎盘细胞类型而异。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY

CiteScore

12.10

自引率

1.30%

发文量

审稿时长

14 weeks

期刊介绍： Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.