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Single-Cell Chromatin Modification Profiling Reveals Increased Epigenetic Variations with Aging
Open accessAbstract
Post-translational modifications of histone proteins and exchanges of histone variants of chromatin are central to the regulation of nearly all DNA-templated biological processes. However, the degree and variability of chromatin modifications in specific human immune cells remain largely unknown. Here, we employ a highly multiplexed mass cytometry analysis to profile the global levels of a broad array of chromatin modifications in primary human immune cells at the single-cell level. Our data reveal markedly different cell-type- and hematopoietic-lineage-specific chromatin modification patterns. Differential analysis between younger and older adults shows that aging is associated with increased heterogeneity between individuals and elevated cell-to-cell variability in chromatin modifications. Analysis of a twin cohort unveils heritability of chromatin modifications and demonstrates that aging-related chromatin alterations are predominantly driven by non-heritable influences. Together, we present a powerful platform for chromatin and immunology research. Our discoveries highlight the profound impacts of aging on chromatin modifications.
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“Reduced levels of H3K122ac extend the lifespan of budding yeast (Sen et al., 2015) and levels of H3K27ac and H3K56ac decrease in many human immune cell types (Cheung et al., 2018; Dang et al., 2009).”
From Loss of epigenetic information as a cause of mammalian aging (2023) · cites this paper as Cheung et al., 2018
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“In line with these findings, increased variation of chromatin modifications was recently observed in immune cells from elderly individuals (18).”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [18]
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Probing infectious disease by single-cell RNA sequencing: Progresses and perspectives
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Production of MHCII ‐expressing classical monocytes increases during aging in mice and humans
Barman, P. K., Shin, J. E., Lewis, S. A., Kang, S., Wu, D., Wang, Y., Yang, X., Nagarkatti, P. S., Nagarkatti, M., Messaoudi, I., et al. (2022) · Aging Cell · doi:10.1111/acel.13701 · Cited by 63
“A Power SYBR Green Cells- to- CT kit was used to isolate RNA and prepare first- strand cDNA from FACS- sorted MDP- derived MHCII+ and MHCII− cells.”
BackgroundInfluentialShchukina, I., Bagaitkar, J., Shpynov, O., Loginicheva, E., Porter, S. I., Mogilenko, D. A., Wolin, E., Collins, P. L., Demidov, G. M., Artomov, M., et al. (2020) · Nature Aging · doi:10.1038/s43587-020-00002-6 · Cited by 60
Wilson, K. A., Chamoli, M., Hilsabeck, T. A. U., Pandey, M., Bansal, S., Chawla, G., & Kapahi, P. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.08.018 · Cited by 57
Galow, A.-M., & Peleg, S. (2022) · Cells · doi:10.3390/cells11030468 · Cited by 60
Temporal changes in the gene expression heterogeneity during brain development and aging
Işıldak, U., Somel, M., Thornton, J. M., & Dönertaş, H. M. (2020) · Scientific Reports · doi:10.1038/s41598-020-60998-0 · Cited by 53
Making use of noise in biological systems
Ilan, Y. (2023) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2023.01.001 · Cited by 58
Nardini, C., Moreau, J., Gensous, N., Ravaioli, F., Garagnani, P., & Bacalini, M. G. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2018.10.009 · Cited by 54
Mapping chromatin modifications at the single cell level
Ludwig, C., & Bintu, L. (2019) · Development · doi:10.1242/dev.170217 · Cited by 55
“EpiTOF was used to measure cell type-specific histone modification patterns that could be used to predict immune cell identity (Cheung et al., 2018).”
BackgroundMethodInfluentialThe metabolite methylglyoxal-mediated gene expression is associated with histone methylglyoxalation
Fu, Z.-W., Li, J., Feng, Y.-R., Yuan, X. H., & Lu, Y. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab014 · Cited by 53
Zhou, J., So, K. K. H., Li, Y., Li, Y., Yuan, J., Ding, Y., Chen, F., Huang, Y., Liu, J., Lee, W., et al. (2019) · Aging Cell · doi:10.1111/acel.12996 · Cited by 52
“Several studies have shown the deregulation of H3K27ac and enhancers in aging tissues/cell types (Benayoun et al., 2018; Cheung et al., 2018; Moskowitz et al., 2017; Ucar et al., 2017).”
BackgroundGlobal metabolic profiling to model biological processes of aging in twins
Bunning, B., Contrepois, K., Lee‐McMullen, B., Dhondalay, G. K., Zhang, W., Tupa, D., Raeber, O., Desai, M., Nadeau, K. C., Snyder, M. P., et al. (2019) · Aging Cell · doi:10.1111/acel.13073 · Cited by 52
“This increased variability with age was also observed in other biological systems such as the immune system (Brodin et al., 2015; Cheung et al., 2018).”
BackgroundLiu, M., Espinosa‐Díez, C., Mahan, S., Du, M., Nguyen, A. T., Hahn, S. A., Chakraborty, R., Straub, A. C., Martin, K. A., Owens, G. K., et al. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.09.001 · Cited by 53
Ty, M., Sun, S., Callaway, P. C., Rek, J. C., Press, K. D., van der Ploeg, K., Nideffer, J., Hu, Z., Klemm, S. L., Greenleaf, W. J., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.add9012 · Cited by 45
“We compared global histone modifications at the single-cell level between CD56dim and CD56neg NK cells using EpiTOF, because these modifications have previously been shown to differentiate CD56bright and CD56dim NK cells (39).”
MethodInfluentialSelf-citationSchijns, V. E. C. J., Majhen, D., van der Ley, P., Thakur, A., Summerfield, A., Berisio, R., Nativi, C., Fernández‐Tejada, A., Alvarez-Domı́nguez, C., Gizurarson, S. S., et al. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13040501 · Cited by 52
Immune Memory in Aging: a Wide Perspective Covering Microbiota, Brain, Metabolism, and Epigenetics
Bulut, O. P., Kılıç, G., & Domínguez‐Andrés, J. (2021) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-021-08905-x · Cited by 50
Targeted DNA methylation profiling reveals epigenetic signatures in peanut allergy
Zhou, X.-Y., Han, X.-R., Lyu, S.-C., Bunning, B., Kost, L., Chang, I., Cao, S., Sampath, V., & Nadeau, K. (2021) · JCI Insight · doi:10.1172/jci.insight.143058 · Cited by 41
“The epigenetic drift during the lifetime of MZ twin 190 pairs has been suggested to arise from differing environmental histories (11, 12).”
BackgroundMechanisms involved in hematopoietic stem cell aging
Fujino, T., Asada, S., Goyama, S., & Kitamura, T. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04356-5 · Cited by 49
“Single-cell analyses revealed that chromatin modifications and DNA methylations became increasingly heterogenous among individual cells with the passage of time [107].”
BackgroundAging and cancer epigenetics: Where do the paths fork?
Pérez, R. F., Tejedor, J. R., Fernández, A. F., & Fraga, M. F. (2022) · Aging Cell · doi:10.1111/acel.13709 · Cited by 44
“…these concerns, systematic metaanalysis studies focusing on multi- tissue common alterations in aging and cancer (Chen et al., 2016; Pérez et al., 2018) and also the use of single- cell epigenetic profiling technologies (Cheung et al., 2018; Hernando- Herraez et al., 2019) are clearly needed.”
BackgroundKedlian, V. R., Dönertaş, H. M., & Thornton, J. M. (2019) · Aging · doi:10.18632/aging.101912 · Cited by 44
Single Cell Omics: From Assay Design to Biomedical Application
Chen, W.-Y., Li, S., Kulkarni, A. S., Huang, L., Cao, J., Qian, K., & Wan, J. (2019) · Biotechnology Journal · doi:10.1002/biot.201900262 · Cited by 42
Epigenetics and the Environment in Airway Disease: Asthma and Allergic Rhinitis
Long, A. J., Bunning, B., Sampath, V., DeKruyff, R. H., & Nadeau, K. C. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-3449-2_6 · Cited by 39
Integrated multi-omics approach revealed cellular senescence landscape
Song, Q., Hou, Y., Zhang, Y., Liu, J., Wang, Y., Fu, J., Zhang, C., Cao, M., Cui, Y., Zhang, X., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac885 · Cited by 44
A Review of Mathematical and Computational Methods in Cancer Dynamics
Uthamacumaran, A., & Zenil, H. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.850731 · Cited by 46
Single-cell technologies — studying rheumatic diseases one cell at a time
Cheung, P., Khatri, P., Utz, P. J., & Kuo, A. J. (2019) · Nature Reviews Rheumatology · doi:10.1038/s41584-019-0220-z · Cited by 39
Self-citationInfluence of human gut microbiome on the healthy and the neurodegenerative aging
Borrego-Ruiz, A., & Borrego, J. J. (2024) · Experimental Gerontology · doi:10.1016/j.exger.2024.112497 · Cited by 43
Epigenetic Regulation of Aging and its Rejuvenation
An, Y., Wang, Q., Gao, K., Zhang, C., Ouyang, Y., Li, R., Zhou, M., Wu, T., Zhou, L., Xie, Z., et al. (2025) · MedComm · doi:10.1002/mco2.70369 · Cited by 47
Single-cell epigenetics – Chromatin modification atlas unveiled by mass cytometry
Cheung, P., Vallania, F., Dvorak, M., Chang, S. E., Schaffert, S. A., Donato, M., Rao, A., Mao, R., Utz, P. J., Khatri, P., et al. (2018) · Clinical Immunology · doi:10.1016/j.clim.2018.06.009 · Cited by 40
“The development of new single-cell analytic platforms, such as bisulfite sequencing to measure DNA methylation [49, 50], ATAC-seq to measure chromatin accessibility [51, 52], chromosome conformation capture (3C) to measure chromatin spatial organization [53], and now EpiTOF to measure global levels of chromatin marks…”
BackgroundSelf-citationWu, O., Jin, Y., Zhang, Z., Zhou, H., Xu, W., Chen, L., Jones, M. E. B., Kwan, K. Y.-H., Gao, J., Zhang, K., et al. (2024) · Bone Research · doi:10.1038/s41413-024-00373-1 · Cited by 43
Tools and Concepts for Interrogating and Defining Cellular Identity
McKinley, K. L., Castillo‐Azofeifa, D., & Klein, O. D. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.03.015 · Cited by 37
“…has since been extended beyond cell surface antigens, allowing immune cells to be distinguished based on their global histone modification profiles (EpiTOF; Cheung et al., 2018) as well as to assess features of cellular metabolism (single-cell metabolic profiling [scMEP]; Hartmann et al., 2020).”
Background
Metadata
- Authors
- Cheung, P., Vallania, F., Warsinske, H. C., Donato, M., Schaffert, S., Chang, S. E., Dvorak, M., Dekker, C. L., Davis, M. M., Utz, P. J., Khatri, P., & Kuo, A. J.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Utz, Paul J.
- Khatri, Purvesh
- Kuo, Alex J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 173
- Issue
- 6
- Pages
- 1385-1397.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5984186
- OpenAlex
- W2801503232
- Cited by
- 323
- References
- 66
- Citations by year
- 2026: 21 · 2025: 27 · 2024: 31 · 2023: 40 · 2022: 40 · 2021: 47 · 2020: 56 · 2019: 35 · 2018: 25
- FWCI
- 14.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 395 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cooperative Center for Human Immunology (U19AI057229)
- NIH (S10RR025518-01, S10RR027431-01, S10OD016318-01, 5U19AI109662-05, 5R01AI125197-02, 5U19AI057229-15, U19AI090019, 2T32AR050942-06A1, 5K12HL120001-02, 5T32AI07290-31, 5T32AI007290-29)
- Autoimmunity Center of Excellence (5U19AI110491-04, 5UM1A110498-04)
- NIAID/NIH
- Bill & Melinda Gates Foundation
- Donald E. and Delia B. Baxter Foundation
- Elizabeth F. Adler
- Henry Gustav Floren Trust
- NIH Clinical and Translational Science Award (UL1 RR025744)
- Novo Nordisk
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- chromatin modification, histone modifications, histone variants, aging, immune cells, single-cell profiling, mass cytometry, hematopoietic lineage, cellular heterogeneity, heritability, twin cohort, epigenetic variation
- MeSH terms
- Adolescent, Adult, Aged, Aging, Cell Separation, Chromatin, Diseases in Twins, Female, Flow Cytometry, Histones, Humans, Immune System, Leukocytes, Mononuclear, Male, Middle Aged, Monocytes, Protein Processing, Post-Translational, Registries, Immunophenotyping, Cell Lineage, Principal Component Analysis, Epigenesis, Genetic, Young Adult
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