Biology subjects

Sebire, N. J.

Publications and source records attributed to Sebire, N. J..

4 recordsLinked to original sources

bioRxiv2025

Spatially resolved fetal and maternal cell contributions to severe Preeclampsia

The molecular and cellular pathophysiology of the fetal-maternal interface in preeclamsia remains poorly understood, but it is increasingly clear that both fetus and mother make independent contributions to it. Here, we spatially distinguish them from each other and from gestational age for the severe form of the disease, interrogating tissues and cell types beyond the placenta for the Early and Late presentation of the condition. In addition to concerted hypoxia, angiogenic imbalance, fibrosis and aberrant metabolism in the placenta, new maternal immune signatures, including changes in macrophages, mitochondrial dysfunction and interferon signalling in the placenta, myometrium or chorioamniotic membranes, offer an explanation to systemic inflammation and endothelial dysfunction in the mother. These tissue and cell-specific responses are potential targets for therapy, with their prompt consideration in Early gestational disease likely beneficial due to its severity. Thus, timely intervention during gestation could change the extremely poor prognosis of severe disease.

molecular biology↗

bioRxiv2024

The transcriptomic landscape of monosomy X (45,X) during early human fetal and placental development

Monosomy X (45,X) is associated with Turner syndrome and pregnancy loss in humans, but the underlying mechanisms remain unclear. We therefore analyzed the transcriptomic landscape of clinically relevant human fetal 45,X tissues (including pancreas, liver, kidney, skin, placenta) with matched 46,XX and 46,XY control samples between 11-15 weeks post conception (n=78). Although most pseudoautosomal region 1 (PAR1) genes were lower in monosomy X tissues, we also found reduced expression of several key genes escaping X inactivation (e.g., KDM5C and KDM6A), and potentially clinically important transcripts such as genes implicated in ascending aortic aneurysm. In contrast, higher expression of an autosomal, long non-coding RNA (OVCH1-AS1) was seen in all 45,X tissues. In the placenta, lower expression of CSF2RA was demonstrated, likely contributing to immune dysregulation. Taken together, these findings provide novel insights into the biological consequences of a single X chromosome during early human development and potential insights in genetic mechanisms in Turner syndrome.

genetics↗

bioRxiv2020

Tumor to normal single cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Neuroblastoma is an embryonal childhood cancer that arises from aberrant development of the neural crest, mostly within the fetal adrenal medulla. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n=16,591) with fetal adrenal single cell transcriptomes (n=57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients and clinical phenotypes. We substantiated our findings in 652 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that there exists a pan-neuroblastoma cancer cell state which may be an attractive target for novel therapeutic avenues.

cancer biology↗

bioRxiv2019

Inherited duplications of PPP2R3B promote naevi and melanoma via a novel C21orf91-driven proliferative phenotype

The majority of the heredity of melanoma remains unexplained, however inherited copy number changes have not yet been systematically studied. The genetic environment is highly relevant to treatment stratification, and new gene discovery is therefore desirable. Using an unbiased whole genome screening approach for copy number we identify here a novel melanoma predisposing factor, familial duplications of gene PPP2R3B, encoding a regulatory unit of critical phosphatase PP2A. Significant correlation between expression of PPP2R3B in tumour tissue and survival in a large melanoma cohort was confirmed, and associated with a non-immunological expression profile. Mechanistically, construction and extensive characterization of a stable, inducible cellular model for PPP2R3B overexpression revealed induction of pigment cell switching towards proliferation and away from migration. Importantly, this was independent of the known microphthalmia-associated transcription factor (MITF)-controlled pigment cell phenotype switch, and was instead driven by uncharacterised gene C21orf91. Bioinformatic studies point to C21orf91as a novel target of MITF, and therefore a potential hub in the control of phenotype switching in melanoma. This study identifies novel germline copy number variants in PPP2R3B predisposing to melanocytic neoplasia, and uncovers a new potential therapeutic target C21orf91 in the control of pigment cell proliferation.

genomics↗