| Autor: |
Ahern DT; Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT 06030.; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT 06030., Bansal P; Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT 06030.; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT 06030., Armillei MK; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT 06030., Faustino IV; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT 06030., Kondaveeti Y; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT 06030., Glatt-Deeley HR; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT 06030., Banda EC; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT 06030., Pinter SF; Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT 06030.; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT 06030.; Institute for Systems Genomics, University of Connecticut, Farmington, CT 06269. |
| Abstrakt: |
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. |
