Sex-based disparities in DNA methylation and gene expression in late-gestation mouse placentas.

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-01-06 DOI:10.1186/s13293-023-00577-w
Lisa-Marie Legault, Mélanie Breton-Larrivée, Alexandra Langford-Avelar, Anthony Lemieux, Serge McGraw
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Abstract

Background: The placenta is vital for fetal development and its contributions to various developmental issues, such as pregnancy complications, fetal growth restriction, and maternal exposure, have been extensively studied in mice. The placenta forms mainly from fetal tissue and therefore has the same biological sex as the fetus it supports. Extensive research has delved into the placenta's involvement in pregnancy complications and future offspring development, with a notable emphasis on exploring sex-specific disparities. However, despite these investigations, sex-based disparities in epigenetic (e.g., DNA methylation) and transcriptomic features of the late-gestation mouse placenta remain largely unknown.

Methods: We collected male and female mouse placentas at late gestation (E18.5, n = 3/sex) and performed next-generation sequencing to identify genome-wide sex differences in transcription and DNA methylation.

Results: Our comparison between male and female revealed 358 differentially expressed genes (DEGs) on autosomes, which were associated with signaling pathways involved in transmembrane transport and the responses to viruses and external stimuli. X chromosome DEGs (n = 39) were associated with different pathways, including those regulating chromatin modification and small GTPase-mediated signal transduction. Differentially methylated regions (DMRs) were more common on the X chromosomes (n = 3756) than on autosomes (n = 1705). Interestingly, while most X chromosome DMRs had higher DNA methylation levels in female placentas and tended to be included in CpG dinucleotide-rich regions, 73% of autosomal DMRs had higher methylation levels in male placentas and were distant from CpG-rich regions. Several DEGs were correlated with DMRs. A subset of the DMRs present in late-stage placentas were already established in mid-gestation (E10.5) placentas (n = 348 DMRs on X chromosome and 19 DMRs on autosomes), while others were acquired later in placental development.

Conclusion: Our study provides comprehensive lists of DEGs and DMRs between male and female that collectively cause profound differences in the DNA methylation and gene expression profiles of late-gestation mouse placentas. Our results demonstrate the importance of incorporating sex-specific analyses into epigenetic and transcription studies to enhance the accuracy and comprehensiveness of their conclusions and help address the significant knowledge gap regarding how sex differences influence placental function.

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妊娠晚期小鼠胎盘中 DNA 甲基化和基因表达的性别差异
背景:胎盘对胎儿的发育至关重要,胎盘对各种发育问题(如妊娠并发症、胎儿生长受限和母体暴露)的影响已在小鼠中得到广泛研究。胎盘主要由胎儿组织形成,因此与其所支持的胎儿具有相同的生物学性别。研究人员对胎盘参与妊娠并发症和后代发育的情况进行了广泛的研究,重点是探索性别差异。然而,尽管进行了这些研究,小鼠妊娠晚期胎盘在表观遗传学(如 DNA 甲基化)和转录组学特征方面的性别差异在很大程度上仍然是未知的:方法:我们收集了妊娠晚期(E18.5,n = 3/性别)的雄性和雌性小鼠胎盘,并进行了新一代测序,以确定转录和DNA甲基化的全基因组性别差异:结果:我们对雌雄胎儿进行了比较,发现常染色体上有358个差异表达基因(DEGs),这些基因与信号通路有关,涉及跨膜运输以及对病毒和外部刺激的反应。X 染色体 DEGs(n = 39)与不同的途径有关,包括调节染色质修饰和小 GTP 酶介导的信号转导的途径。与常染色体(n = 1705)相比,X 染色体上的差异甲基化区域(DMRs)更常见(n = 3756)。有趣的是,虽然大多数 X 染色体 DMR 在女性胎盘中的 DNA 甲基化水平较高,而且往往包含在 CpG 二核苷酸丰富的区域中,但 73% 的常染色体 DMR 在男性胎盘中的甲基化水平较高,而且远离 CpG 丰富的区域。一些 DEGs 与 DMRs 相关。出现在晚期胎盘中的 DMRs 子集已在妊娠中期(E10.5)胎盘中建立(X 染色体上有 348 个 DMRs,常染色体上有 19 个 DMRs),而其他 DMRs 则是在胎盘发育后期获得的:我们的研究提供了雌雄胎盘间 DEGs 和 DMRs 的综合列表,这些 DEGs 和 DMRs 共同导致了晚期妊娠小鼠胎盘 DNA 甲基化和基因表达谱的深刻差异。我们的研究结果表明了将性别特异性分析纳入表观遗传学和转录研究的重要性,以提高其结论的准确性和全面性,并帮助解决有关性别差异如何影响胎盘功能的重大知识空白。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
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.
期刊最新文献
Sex differences in the role of AKAP12 in behavioral function of middle-aged mice. Sex differences in the human brain related to visual motion perception. A call for inclusive research, policies, and leadership to close the global women's health gap. Sex differences in contextual fear conditioning and extinction after acute and chronic nicotine treatment. Sex dimorphism and tissue specificity of gene expression changes in aging mice.
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