SEX differences in allelic gene regulation in human placenta

The National Institute of Child Health and Human Development awarded the University of Washington $564,830 on June 15, 2026, under the Child Health and Human Development Extramural Research Projects program (CFDA 93.HDR) to investigate sex differences in allelic gene regulation in human placenta.

The research examines how sex chromosome dosage influences allelic gene regulation during placental development and trophoblast differentiation. The project determines whether sex chromosome imbalances—arising from X chromosome inactivation and Y-linked gene expression—contribute to sex-biased outcomes in pregnancy, including male-associated gestational diabetes and placental abruption and female-associated fetal growth restriction and preeclampsia. The work combines ex vivo and in vitro approaches using single-nuclei and single-cell assays alongside multi-omics and functional studies to identify sex-linked candidate genes affecting placental health and function.

The University of Washington's Office of Sponsored Programs serves as the recipient. Performance occurs in Seattle, Washington, with a period of performance from June 15, 2026, through February 28, 2031.

Abstract

The goals of this project are to determine how SEX chromosome dosage (SCD) influences allelic gene regulation in the context of placental development and how SCD imbalance leads to impaired trophoblast differentiation and placental health and function. One fundamental difference between males and females is the SEX chromosome content (46,XY and 46,XX), which causes imbalances in X/Y expression. While X chromosome inactivation (XCI) specifically silences one X chromosome in females to restore balanced expression, some genes escape XCI and thus have female-biased expression. In addition, Y-linked genes are only expressed in males. Prior to the onset of SEX hormones, the effects of SCD on SEX differences in autosomal gene expression and phenotypes are largely mediated by the dosage of SEX-linked genes, especially X- and Y- paralogs. Notably, there is a marked effect of fetal SEX on pregnancy outcomes. For example, carrying a male fetus is associated with increased risk of gestational diabetes and placental abruption, while carrying a female fetus is associated with increased risk of fetal growth restriction and preeclampsia. Allelic gene expression in males and females contributes to fetal SEX differences. However, whether SCD contributes to allele-biased gene expression in placental development remains unknown. We previously showed that manipulation of X-linked gene dosage in mouse results in dysregulation of allelic gene expression. To determine the overall impact of differential SCD on allelic gene regulation and identify SEX- linked candidate genes in human placental development as well as during trophoblast differentiation, we will use complementary EX vivo and in vitro approaches to leverage integrated multi-omics and functional studies. First, we will determine the effects of X- and Y-chromosome gene dosage on allelic gene regulation by single- nuclei and single cell assays performed in human 1ST trimester placental tissue with varied SEX chromosome content (aim 1) and in trophoblast cell models derived from a unique collection of isogenic human induced pluripotent stem cells (HIPSCS) with different numbers of SEX chromosomes (aim 2). Second, we will investigate mechanisms controlling allelic gene expression by modulating the expression of SEX-linked candidate X/Y paralogs and using allelic transcriptomic and epigenomic analyses to identify critical pathways (aim 3). Third, functional assays will be carried out to evaluate phenotypic effects of differential SCD on trophoblast and trophoblast organoid function (aims 2 and 3). Overall, this work will provide a comprehensive view of the effects of differential SCD on allele-specific gene regulation and on placental health and function. Results from this project will address a GAP in our knowledge of the mechanisms underlying SEX differences in allelic gene regulation at the fetal-maternal interface.