Abstract 7016: Plastic epigenome in youth: Insights from open chromatin in stem cells

Abstract

Abstract The presence of plasticity in the epigenomes of young individuals is suggested by the aggressive phenotypes observed in cancers among adolescent and young adults (AYAs), including gastric cancers. To demonstrate the presence of this plasticity and identify the underlying epigenomic characteristics in gastric stem cells during youth, we examined organoids established from murine stomach tissue and conducted single-cell RNA-seq and ATAC-seq using murine antrum-pyloric tissues at ages of 3 weeks and 50 weeks, corresponding to human infancy and middle-age adult, respectively. Organoids established from infant mice showed higher dependence to niche factors, and stronger response to cytokine signals. Ligand-receptor analysis using single-cell RNA-seq data of tissues showed that infant epithelial stem cells and stromal cells had stronger interactions. Both supported the plastic nature of infant gastric epithelial cells. Single-cell ATAC-seq enabled us to identify epithelial stem cell population in infant and middle-aged mice, and 71 and 118 chromatin peaks were specific to infant and adult stem cells, respectively. Motif enrichment analysis showed an enrichment of binding sites for bZIP family transcription factors in infants, and an enrichment of binding sites of a chromatin remodeling factor and a family of transcription factors in adults. Additionally, comparison between differentiated epithelial cells, marked by the pit cell marker Muc5ac, and stem cells, marked by Lgr5, showed more pronounced differences: 46,772 peaks specific to pit cells and 39,076 peaks specific to stem cells. Interestingly, regions specific to pit cells were enriched in binding sites of the chromatin remodeling factor and the family of transcription factors, identical to the open regions specific to adult stem cells. This suggested that the chromatin accessibility profile of aged stem cells approaches to that of differentiated cells, leading to a loss of stemness. The single-cell RNA-seq data also revealed an increase in interactions between differentiated epithelial cells and fibroblasts in aged mice, as opposed to infant, suggesting the emergence of aberrant interactions in aged stomach tissue. Collectively, our data suggested that chromatin accessibility of gastric stem cells undergo an epigenomic shift during aging, approaching to the profiles of differentiated cells and losing their plasticity, and that a specific chromatin remodeling factor and a family of transcription factors could be involved in the process. Citation Format: Yu-Yu Liu, Chihiro Takeuchi, Satoshi Yamashita, Toshikazu Ushijima. Plastic epigenome in youth: Insights from open chromatin in stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7016.