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Examining Sex Differences in the Human Placental Transcriptome During the First Fetal Androgen Peak

  • Maternal Fetal Medicine/Biology: Original Article
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Abstract

Sex differences in human placenta exist from early pregnancy to term, however, it is unclear whether these differences are driven solely by sex chromosome complement or are subject to differential sex hormonal regulation. Here, we survey the human chorionic villus (CV) transcriptome for sex-linked signatures from 11 to 16 gestational weeks, corresponding to the first window of increasing testis-derived androgen production in male fetuses. Illumina HiSeq RNA sequencing was performed on Lexogen Quantseq 3′ libraries derived from CV biopsies (n = 11 females, n = 12 males). Differential expression (DE) was performed to identify sex-linked transcriptional signatures, followed by chromosome mapping, pathway analysis, predicted protein interaction, and post-hoc linear regressions to identify transcripts that trend over time. We observe 322 transcripts DE between male and female CV from 11 to 16 weeks, with 22 transcripts logFC > 1. Contrary to our predictions, the difference between male and female expression of DE autosomal genes was more pronounced at the earlier gestational ages. In females, we found selective upregulation of extracellular matrix components, along with a number of X-linked genes. In males, DE transcripts centered on chromosome 19, with mitochondrial, immune, and pregnancy maintenance-related transcripts upregulated. Among the highest differentially expressed autosomal genes were CCRL2, LGALS13, and LGALS14, which are known to regulate immune cell interactions. Our results provide insight into sex-linked gene expression in late first and early second trimester developing human placenta and lay the groundwork to understand the mechanistic origins of sex differences in prenatal development.

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Data Availability

Raw and processed RNA sequencing data are available via the Gene Expression Omnibus (GEO) repository GSE160076.

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Acknowledgments

The authors would like to acknowledge Stanford’s WHSDM center, Dr. Marcia Stefanick, and Stanford’s Center for Genomics and Personalized Medicine for assisting this work.

Funding

This work was supported by a pilot grant to VDW, TDP, and AEB by the center for Women’s Health and Sex Differences in Medicine (WHSDM) at Stanford University, MCHRI Postdoctoral Fellowship (AEB) Stanford Dean’s Postdoctoral Fellowhip (AEB) the H&H Evergreen Fund (VDW), Harman Faculty Scholar MCHRI (VDW). University of Colorado Department of OBGYN Academic Enrichment Grant (VDW), Basil O’Conner award (VDW).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Dr. H333, Stanford, CA, 94305-5317, USA

    Amy E. Braun, Angela Wang & Virginia D. Winn

  2. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive, Rm 1141, Stanford, CA, 94305-5454, USA

    Amy E. Braun, Kristin L. Muench, Beatriz G. Robinson & Theo D. Palmer

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  1. Amy E. Braun
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  2. Kristin L. Muench
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  3. Beatriz G. Robinson
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  4. Angela Wang
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  5. Theo D. Palmer
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  6. Virginia D. Winn
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Contributions

VDW supplied CV biopsies, AEB performed RNA isolation and library preparation. BGR and AEB performed alignment and read counting, KLM performed limma analysis, AEB performed all downstream analyses, AEB and KLM created the figures, AEB wrote the manuscript. AEB, KLM, BGR, AW, TDP, and VDW made intellectual contributions to the project.

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Correspondence to Amy E. Braun.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

Placental samples were obtained from elective terminations under IRB-approved protocols at the University of Colorado for use of discarded tissue. No patient consents are required for use of discarded placental tissue, and all tissue was collected prior to the 07/19/2019 release of NIH policy NOT-OD-19-128.

Code Availability

Code for bioinformatic analyses in this paper are available at www.github.com/kmuench/abraun_placentaGeneSwitch.

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Braun, A.E., Muench, K.L., Robinson, B.G. et al. Examining Sex Differences in the Human Placental Transcriptome During the First Fetal Androgen Peak. Reprod. Sci. 28, 801–818 (2021). https://doi.org/10.1007/s43032-020-00355-8

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