Abstract IA011: Heterochromatin deregulation during hematopoietic stem progenitor cell (HSPC) aging

Abstract Aging is one of the major negative factors affecting normal hematopoiesis. Aged hematopoietic stem and progenitor cells (HSPCs) exhibit reduced self-renewal and increased myeloid bias during lineage specification, thereby sabotaging the immune system and increasing the risk of malignant transformation. Epigenetic dysregulation is a hallmark feature of aging and significantly contributes to age-related dysfunction across multiple biological systems. DNA methylation drift is commonly observed during aging, especially within late-replicated heterochromatin. DNA methylation and demethylation are maintained by DNMT and TET enzymes. Mutations in DNMT3A and TET2 are frequently observed in age-related clonal hematopoiesis (CH) and hematological malignancies. The impact of DNMT3A or TET2 loss-of-function on heterochromatin has recently gained recognition. Although heterochromatin is generally regarded as a gene-less region, it plays an important role in maintaining genome stability. Recently, we compared the impact of aging on WT and Tet2 knockout (KO) HSPCs. We observed that aging has less impact on Tet2KO HSPCs, which retain considerable clonal expansion capability during aging. However, WT HSPCs exhibited functional decline with age. At the molecular level, we identified the spatial relocation of heterochromatin from the nuclear periphery to the intranuclear region in aged WT HSPCs, but not in Tet2KO HSPCs. This relocation resulted in the upregulation of endogenous retroviruses (ERVs) and the promotion of innate immune responses in WT HSPCs, contributing to their functional decline during aging. This study adds a new dimension to understanding the functional interplay between DNA methylation and histone modifications in maintaining heterochromatin integrity and genome stability during stem cell aging. Citation Format: Tingting Hong, Lei Guo, Anna Guzman, James You, Margaret Goodell, Yubin Zhou, Yun Huang. Heterochromatin deregulation during hematopoietic stem progenitor cell (HSPC) aging [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr IA011