TET2 Modulates Spatial Relocalization of Heterochromatin in Aged Hematopoietic Stem and Progenitor Cells

Authors

Tingting Hong
Jia Li
Lei Guo
Maryn Cavalier
Tianlu Wang
Yaling Dou
Aaron DeLaFuente
Shaohai Fang
Anna Guzman
Katherina Wohlan
Chiraag Kapadia
Carina Rosas
Yaling Yang
C Cameron Yin
Shaoying Li
M James You
Xiaodong Cheng
Margaret A Goodell
Yubin Zhou
Yun Huang

Publication Date

11-1-2023

Journal

Nature Aging

Abstract

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-related clonal expansion. Reverse transcriptase inhibitors suppress ERVs and ISGs expression, thereby restoring age-related defects in aged HSPCs. Collectively, our findings deepen the understanding of the functional interplay between DNA methylation and histone modifications, which is vital for maintaining heterochromatin function and safeguarding genome stability in stem cells.

Keywords

Heterochromatin, Hematopoietic Stem Cells, DNA Methylation

Comments

Associated Data

PMID: 37884767