SFEIES24 Poster Presentations Reproductive Endocrinology (15 abstracts)
Single-nucleus rna-sequencing reveals novel potential mechanisms of ovarian insufficiency in 45,x turner syndrome
Sinead McGlacken-Byrne 1 , Ignacio Del Valle 1 , Theodoros Xenakis 1 , Jenifer P. Suntharalingham 1 , Lydia Nel 2 , Danielle Liptrot 2 , Berta Crespo 2 , Olumide K. Ogunbiyi 2,3 , Paola Niola 4 , Tony Brooks 4 , Nita Solanky 2 , Gerard S. Conway 5 & John C. Achermann 1
1Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; 2Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; 3Department of Histopathology, Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London, United Kingdom; 4UCL Genomics, Zayed Centre for Research, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; 5Institute for Women’s Health, University College London, London, United Kingdom
Background: Turner syndrome (TS) is the most common genetic cause of Primary Ovarian Insufficiency (POI). Morphological analyses of human fetal 45,X ovaries have demonstrated germ cell apoptosis by 15-20 weeks post conception (wpc). However, we do not know why POI develops mechanistically. Here, we use single-nuclei RNA sequencing (snRNA-seq) and bulk RNA sequencing to identify novel potential mechanisms of ovarian insufficiency in TS and to characterise X chromosome gene expression in 45,X ovaries.
Methods: We performed snRNA-seq of peri-meiotic 46,XX (n = 2) and 45,X (n = 2) fetal ovaries at 12-13 wpc; and 2) a bulk RNA sequencing time-series analysis of fetal ovary, testis, and control samples across four developmental timepoints (n = 47; Carnegie Stage 22-16wpc).
Results: Germ and somatic cell subpopulations were mostly shared across 46,XX and 45,X ovaries, aside from a 46XX-specific/45,X-depleted cluster of oogonia (“synaptic oogonia”) containing genes related to sex chromosome synapsis; histone modification; intracellular protein regulation and chaperone systems. snRNA-seq enabled accurate cell counting within individual cell clusters; the 45,X ovary has fewer germ cells than the 46,XX ovary in every germ cell subpopulation, confirmed histopathologically. Normal X-chromosome inactivation/reactivation is disrupted in 45,X ovaries; XIST was not expressed in 45,X somatic cells but was present in germ cell clusters, albeit with lower expression than in 46,XX clusters. The 45,X ovary has a globally abnormal transcriptome, with low expression of genes related to proteostasis (RSP4X); cell cycle progression (BUB1B); and OXPHOS mitochondrial energy production (COX6C, ATP11C). Genes with higher expression in 45,X cell populations were enriched for apoptotic functions (e.g., NR4A1).
Discussion: We characterise the human fetal peri-meiotic 45,X ovary at single-cell resolution and offer insights into potential novel pathogenic mechanisms underlying ovarian insufficiency in TS beyond X-chromosome haploinsufficiency. We suggest ovarian insufficiency in TS may be a combinatorial process characterised by periods of vulnerability throughout early germ cell development.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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