High-throughput mRNA sequencing of human placenta shows sex differences across gestation

Amy E Flowers; Tania L Gonzalez; Yizhou Wang; Chintda Santiskulvong; Ekaterina L Clark; Allynson Novoa; Caroline A Jefferies; Kate Lawrenson; Jessica L Chan; Nikhil V Joshi; Yazhen Zhu; Hsian-Rong Tseng; Erica T Wang; Mariko Ishimori; S Ananth Karumanchi; John Williams 3rd; Margareta D Pisarska

doi:10.1016/j.placenta.2024.03.005

High-throughput mRNA sequencing of human placenta shows sex differences across gestation

Placenta. 2024 May:150:8-21. doi: 10.1016/j.placenta.2024.03.005. Epub 2024 Mar 21.

Authors

Amy E Flowers¹, Tania L Gonzalez¹, Yizhou Wang², Chintda Santiskulvong³, Ekaterina L Clark¹, Allynson Novoa¹, Caroline A Jefferies⁴, Kate Lawrenson⁵, Jessica L Chan⁶, Nikhil V Joshi¹, Yazhen Zhu⁷, Hsian-Rong Tseng⁸, Erica T Wang⁶, Mariko Ishimori⁹, S Ananth Karumanchi⁹, John Williams 3rd⁶, Margareta D Pisarska¹⁰

Affiliations

¹ Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
² Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
³ CS Cancer Applied Genomics Shared Resource, CS Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
⁴ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
⁵ Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁶ Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁷ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA; California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁸ California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁹ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
¹⁰ Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: Margareta.Pisarska@cshs.org.

PMID: 38537412
DOI: 10.1016/j.placenta.2024.03.005

Abstract

Introduction: Fetal sex affects fetal and maternal health outcomes in pregnancy, but this connection remains poorly understood. As the placenta is the route of fetomaternal communication and derives from the fetal genome, placental gene expression sex differences may explain these outcomes.

Objectives: We utilized next generation sequencing to study the normal human placenta in both sexes in first and third trimester to generate a normative transcriptome based on sex and gestation.

Study design: We analyzed 124 first trimester (T1, 59 female and 65 male) and 43 third trimester (T3, 18 female and 25 male) samples for sex differences within each trimester and sex-specific gestational differences.

Results: Placenta shows more significant sexual dimorphism in T1, with 94 T1 and 26 T3 differentially expressed genes (DEGs). The sex chromosomes contributed 60.6% of DEGs in T1 and 80.8% of DEGs in T3, excluding X/Y pseudoautosomal regions. There were 6 DEGs from the pseudoautosomal regions, only significant in T1 and all upregulated in males. The distribution of DEGs on the X chromosome suggests genes on Xp (the short arm) may be particularly important in placental sex differences. Dosage compensation analysis of X/Y homolog genes shows expression is primarily contributed by the X chromosome. In sex-specific analyses of first versus third trimester, there were 2815 DEGs common to both sexes upregulated in T1, and 3263 common DEGs upregulated in T3. There were 7 female-exclusive DEGs upregulated in T1, 15 female-exclusive DEGs upregulated in T3, 10 male-exclusive DEGs upregulated in T1, and 20 male-exclusive DEGs upregulated in T3.

Discussion: This is the largest cohort of placentas across gestation from healthy pregnancies defining the normative sex dimorphic gene expression and sex common, sex specific and sex exclusive gene expression across gestation. The first trimester has the most sexually dimorphic transcripts, and the majority were upregulated in females compared to males in both trimesters. The short arm of the X chromosome and the pseudoautosomal region is particularly critical in defining sex differences in the first trimester placenta. As pregnancy is a dynamic state, sex specific DEGs across gestation may contribute to sex dimorphic changes in overall outcomes.

Keywords: Abbreviations: CVS; Benjamini-Hochberg false discovery rate; Chorionic villus sampling; DEGs; Differentially expressed genes; FC; FDR; First trimester; Fold change; Gestational differences; High-throughput mRNAseq; Human placenta; IPA; Ingenuity pathway analysis; Next generation sequencing; Normative atlas; PAR; PCA; Principal components analysis; Pseudoautosomal region; Sex differences; T1; T3; TPM; Third trimester; Transcriptome; Transcripts per million.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adult
Female
High-Throughput Nucleotide Sequencing*
Humans
Male
Placenta* / metabolism
Pregnancy
Pregnancy Trimester, First / genetics
Pregnancy Trimester, First / metabolism
Pregnancy Trimester, Third / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism
Sequence Analysis, RNA
Sex Characteristics*
Transcriptome

Substances

RNA, Messenger