[R01] Sex differences in allelic gene regulation in human placenta
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2031-02-28
Importo max: 564.830 EUR
Paese: US
Descrizione
Project Summary:
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.
Istituzione: UNIVERSITY OF WASHINGTON
PI: JOEL Bradford BERLETCH
Progetto: 1R01HD119026-01A1
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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