TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells

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

doi:10.1038/s43587-023-00505-y

TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells

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

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1387-1400
Number of pages	14
Journal	Nature Aging
Volume	3
Issue number	11
DOIs	https://doi.org/10.1038/s43587-023-00505-y
State	Published - Nov 2023

ASJC Scopus subject areas

Neuroscience (miscellaneous)
Aging
Geriatrics and Gerontology

Access to Document

10.1038/s43587-023-00505-y

Cite this

Hong, T., Li, J., Guo, L., Cavalier, M., Wang, T., Dou, Y., DeLaFuente, A., Fang, S., Guzman, A., Wohlan, K., Kapadia, C., Rosas, C., Yang, Y., Yin, C. C., Li, S., You, M. J., Cheng, X., Goodell, M. A., Zhou, Y., & Huang, Y. (2023). TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells. Nature Aging, 3(11), 1387-1400. https://doi.org/10.1038/s43587-023-00505-y

Hong, T, Li, J, Guo, L, Cavalier, M, Wang, T, Dou, Y, DeLaFuente, A, Fang, S, Guzman, A, Wohlan, K, Kapadia, C, Rosas, C, Yang, Y , Yin, CC , Li, S , You, MJ , Cheng, X, Goodell, MA, Zhou, Y & Huang, Y 2023, 'TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells', Nature Aging, vol. 3, no. 11, pp. 1387-1400. https://doi.org/10.1038/s43587-023-00505-y

@article{17eb61c84f6d480e853ad0616a5296b5,

title = "TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = nov,

doi = "10.1038/s43587-023-00505-y",

language = "English (US)",

volume = "3",

pages = "1387--1400",

journal = "Nature Aging",

issn = "2662-8465",

publisher = "Springer",

number = "11",

}

TY - JOUR

T1 - TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells

AU - Hong, Tingting

AU - Li, Jia

AU - Guo, Lei

AU - Cavalier, Maryn

AU - Wang, Tianlu

AU - Dou, Yaling

AU - DeLaFuente, Aaron

AU - Fang, Shaohai

AU - Guzman, Anna

AU - Wohlan, Katherina

AU - Kapadia, Chiraag

AU - Rosas, Carina

AU - Yang, Yaling

AU - Yin, C. Cameron

AU - Li, Shaoying

AU - You, M. James

AU - Cheng, Xiaodong

AU - Goodell, Margaret A.

AU - Zhou, Yubin

AU - Huang, Yun

PY - 2023/11

Y1 - 2023/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85174956294&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85174956294&partnerID=8YFLogxK

U2 - 10.1038/s43587-023-00505-y

DO - 10.1038/s43587-023-00505-y

M3 - Article

C2 - 37884767

AN - SCOPUS:85174956294

SN - 2662-8465

VL - 3

SP - 1387

EP - 1400

JO - Nature Aging

JF - Nature Aging

IS - 11

ER -

TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this