Monosomy X in isogenic human iPSC-derived trophoblast model impacts expression modules preserved in human placenta

Abstract

Mammalian sex chromosomes encode homologous X/Y gene pairs that were retained on the Y chromosome in males and escape X chromosome inactivation (XCI) in females. Inferred to reflect X/Y pair dosage sensitivity, monosomy X is a leading cause of miscarriage in humans with near full penetrance. This phenotype is shared with many other mammals but not the mouse, which offers sophisticated genetic tools to generate sex chromosomal aneuploidy but also tolerates its developmental impact. To address this critical gap, we generated X-monosomic human induced pluripotent stem cells (hiPSCs) alongside otherwise isogenic euploid controls from male and female mosaic samples. Phased genomic variants in these hiPSC panels enable systematic investigation of X/Y dosage-sensitive features using in vitro models of human development. Here, we demonstrate the utility of these validated hiPSC lines to test how X/Y-linked gene dosage impacts a widely used model for human syncytiotrophoblast development. While these isogenic panels trigger a GATA2/3- and TFAP2A/C -driven trophoblast gene circuit irrespective of karyotype, differential expression implicates monosomy X in altered levels of placental genes and in secretion of placental growth factor (PlGF) and human chorionic gonadotropin (hCG). Remarkably, weighted gene coexpression network modules that significantly reflect these changes are also preserved in first-trimester chorionic villi and term placenta. Our results suggest monosomy X may skew trophoblast cell type composition and function, and that the combined haploinsufficiency of the pseudoautosomal region likely plays a key role in these changes.

Isogenic hiPSC models of Turner syndrome development reveal shared roles of inactive X and Y in the human cranial neural crest network

“…4C). While homozygous loss-of-function mutations have revealed PLCXD1 as dispensable in humans 37 , ZBED1 was also the top candidate in our 45,X hiPSC-derived trophoblast analysis 12 .…”

“…4C). While homozygous loss-of-function mutations have revealed PLCXD1 as dispensable in humans 37 , ZBED1 was also the top candidate in our 45,X hiPSC-derived trophoblast analysis 12 . RPS4X was especially notable given that translation was over-represented in its assigned module 6, which was also enriched in the top3-scoring HPO terms associated with TS: ‘Horseshoe kidney’, ‘Coarctation of the aorta’ and ‘Webbed neck’ (Fig.…”

“…(iii) Preservation statistics (integer-rounded Z-score) in transcriptomes of the developing human face 26,27 (Carnegie stages CS13-17 & 22) and heart 25 (CS13-23), alongside hiPSC-derived NCC models of monogenic neurocristopathy syndromes (Pierre-Robin/ SOX9 29 , Waardenburg/ SOX10 28 , Familial Dysautonomia/ IKBKAP 30 , Bohring-Opitz/ ASXL1 31 , Floating-Harbor/ SRCAP 32 , and Branchio-Oculofacial/ TFAP2A 33 ). Monosomy-X human iPSC-derived trophoblast-like cells (TBL 12 ) and pancreatic tumor stroma (Stroma 54 ) were included as positive and negative controls, respectively. (iv) Wald (DESeq2) statistic averaged across genes within each module.…”

“…To address this problem, we derived and cytogenomically validated X-monosomic human induced pluripotent stem cells (hiPSCs) alongside isogenic euploid control lines from mosaic fibroblasts. We recently reported that such isogenic panels from three unrelated donors recapitulate a hypothesized impairment of trophoblast cell fates due to monosomy-X 12 .…”

Comparative cytogenetics of anembryonic pregnancies and missed abortions in human

“…МЕДИЦИНСКАЯ ГЕНЕТИКА / MEDICAL GENETICS a noticeable negative effect on the early development of the embryo per se, and such embryos die at later stages, possibly due to a failure of trophoblast function (Ahern et al, 2022).…”