Epigenetic loss of heterogeneity from low to high grade localized prostate tumours

• Published in: Nature communications 2021-12, Vol.12 (1), p.7292-7292, Article 7292
• Main Authors: Eksi, Sebnem Ece, Chitsazan, Alex, Sayar, Zeynep, Thomas, George V., Fields, Andrew J., Kopp, Ryan P., Spellman, Paul T., Adey, Andrew C.
• Format: Article
• Language: English
• Subjects: 14; 14/63; 38; 38/77; 45; 45/23; 631/208/177; 631/67/2329; 631/67/68; 82/51; 96/47; 96/63; Accessibility; Binding sites; Calcium-Binding Proteins - genetics; CDX2 protein; CDX2 Transcription Factor - genetics; Cell Adhesion Molecules, Neuronal - genetics; Chromatin; Cohort Studies; Epigenesis, Genetic; Epigenetics; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Hepatocyte Nuclear Factor 3-alpha - genetics; Heterogeneity; Homeodomain Proteins - genetics; Humanities and Social Sciences; Humans; Immunofluorescence; Loss of Heterozygosity; Male; multidisciplinary; Neoplasm Staging; Neural Cell Adhesion Molecules - genetics; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Science; Science (multidisciplinary); Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27615-8

Identifying precise molecular subtypes attributable to specific stages of localized prostate cancer has proven difficult due to high levels of heterogeneity. Bulk assays represent a population-average, which mask the heterogeneity that exists at the single-cell level. In this work, we sequence the accessible chromatin regions of 14,424 single-cells from 18 flash-frozen prostate tumours. We observe shared chromatin features among low-grade prostate cancer cells are lost in high-grade tumours. Despite this loss, high-grade tumours exhibit an enrichment for FOXA1, HOXB13 and CDX2 transcription factor binding sites, indicating a shared trans-regulatory programme. We identify two unique genes encoding neuronal adhesion molecules that are highly accessible in high-grade prostate tumours. We show NRXN1 and NLGN1 expression in epithelial, endothelial, immune and neuronal cells in prostate cancer using cyclic immunofluorescence. Our results provide a deeper understanding of the active gene regulatory networks in primary prostate tumours, critical for molecular stratification of the disease. High tumour heterogeneity hinders the identification of molecular subtypes in prostate cancer. Here, the authors integrate single-cell chromatin accessibility data with multiplex imaging and reveal distinct chromatin features and transcriptional factor binding signatures in high- and low-grade prostate tumours.