biostudies-literatureHong TU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)NIA NIH HHSLeukemia and Lymphoma Society (Leukemia & Lymphoma Society)U.S. Department of Health & Human Services | NIH | National Institute on AgingNHLBI NIH HHSU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood InstituteU.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)NIDDK NIH HHSU.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)Welch FoundationU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)Leukemia and Lymphoma SocietyU.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases1387-1400https://www.ebi.ac.uk/biostudies/studies/S-EPMC11209854biostudies-literatureUnknown3(11)DNA methylation deregulation at partially methylated domains (PMDs) represents an epigenetic signature of aging and cancer, yet the underlying molecular basis and resulting biological consequences remain unresolved. We report herein a mechanistic link between disrupted DNA methylation at PMDs and the spatial relocalization of H3K9me3-marked heterochromatin in aged hematopoietic stem and progenitor cells (HSPCs) or those with impaired DNA methylation. We uncover that TET2 modulates the spatial redistribution of H3K9me3-marked heterochromatin to mediate the upregulation of endogenous retroviruses (ERVs) and interferon-stimulated genes (ISGs), hence contributing to functional decline of aged HSPCs. TET2-deficient HSPCs retain perinuclear distribution of heterochromatin and exhibit age-relatedNature agingTET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells.PMC11209854R35 HL166557P30CA125123BE-1913-20220331LLS-TRP 6680-24P01CA265748R21 CA277257R56 DK092883P01 AG036695R01CA232017P30 CA125123CA183252R01CA240258R01 CA232017R01 DK092883R35HL166557DK092883R21CA277257P01AG036695R01DK132286R01 CA240258R01 CA183252P01 CA265748R01 DK132286Rosas CLi JWohlan KGuzman AKapadia CZhou YCheng XDeLaFuente AYou MJCavalier MDou YGuo LYang YLi SHuang YGoodell MAWang THong TFang SYin CCfalseTET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells.DNA methylation deregulation at partially methylated domains (PMDs) represents an epigenetic signature of aging and cancer, yet the underlying molecular basis and resulting biological consequences remain unresolved. We report herein a mechanistic link between disrupted DNA methylation at PMDs and the spatial relocalization of H3K9me3-marked heterochromatin in aged hematopoietic stem and progenitor cells (HSPCs) or those with impaired DNA methylation. We uncover that TET2 modulates the spatial redistribution of H3K9me3-marked heterochromatin to mediate the upregulation of endogenous retroviruses (ERVs) and interferon-stimulated genes (ISGs), hence contributing to functional decline of aged HSPCs. TET2-deficient HSPCs retain perinuclear distribution of heterochromatin and exhibit age-related2023-01-01T00:00:00Z2023 Nov2026-06-01T21:25:16.65Z2025-04-04T21:22:14.546ZS-EPMC112098543788476710.1038/s43587-023-00505-y