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 H3K122ac extends lifespan of budding yeast, and H3K27ac and H3K56ac decrease in many human immune cell types.
“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
Cheung et al. report the opposite overall age trend: the Results (EpiTOF Reveals Aging-Associated Changes; page unavailable) say the vast majority of chromatin-mark measurements were elevated in older subjects, and the Discussion says most marks increased across a broad array of immune cell subtypes. The Results identify reduced marks in central memory CD8+ T cells as an exception, not a decrease across many immune cell types. The budding-yeast claim is attributed to Sen et al., not Cheung et al. (LLM, conf=0.82)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIncreased variation of chromatin modifications was observed in immune cells from elderly individuals.
“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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Contribution of genetic variation to transgenerational inheritance of DNA methylation
McRae, A. F., Powell, J. E., Henders, A. K., Bowdler, L. M., Hemani, G., Shah, S. H., Painter, J. N., Martin, N. G., Visscher, P. M., & Montgomery, G. W. (2014) · Genome biology · doi:10.1186/gb-2014-15-5-r73 · Cited by 270 · cited 1× · see citing works
“Our findings are highly similar to results from twin analyses on DNA methylation, where environmental influences explain approximately 80% of the variance in DNA methylation (McRae et al., 2014; van Dongen et al., 2016).”
Detection of histone modifications at specific gene loci in single cells in histological sections
Gomez, D., Shankman, L. S., Nguyen, A. T., & Owens, G. K. (2013) · Nature Methods · doi:10.1038/nmeth.2332 · Cited by 253 · cited 2× · see citing works
“…have allowed investigations of chromatin dynamics using a small number of cells or even single cells (Buenrostro et al., 2015; Corces et al., 2016; Gomez et al., 2013; Rotem et al., 2015; Schwartzman and Tanay, 2015), a high-throughput method to measure the overall cellular levels of chromatin…”
Epigenomics of human CD8 T cell differentiation and aging
Moskowitz, D. M., Zhang, D. W., Hu, B., Le Saux, S., Yanes, R. E., Ye, Z., Buenrostro, J. D., Weyand, C. M., Greenleaf, W. J., & Goronzy, J. J. (2017) · Science Immunology · doi:10.1126/sciimmunol.aag0192 · Cited by 252 · cited 1× · see citing works
“Recent reports have found substantial chromatin changes as a result of aging (Moskowitz et al., 2017; Ucar et al., 2017).”
Arvey, A. J., van der Veeken, J., Samstein, R. M., Feng, Y., Stamatoyannopoulos, J. A., & Rudensky, A. Y. (2014) · Nature Immunology · doi:10.1038/ni.2868 · Cited by 242 · see citing works
The chromatin accessibility signature of human immune aging stems from CD8+ T cells
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“Recent reports have found substantial chromatin changes as a result of aging (Moskowitz et al., 2017; Ucar et al., 2017).”
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“While the CD56bright subset is historically considered the precursor of CD56dim NK cells, recent evidence suggests that the two subsets differentiate from independent hematopoietic lineages (Wu et al., 2014).”
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Self-citationCritical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation
Li, Q., Zou, J., Wang, M., Ding, X., Chepelev, I., Zhou, X., Zhao, W., Wei, G., Cui, J., Zhao, K., et al. (2014) · Nature Communications · doi:10.1038/ncomms6780 · Cited by 156 · cited 5× · see citing works
“We found that in addition to the upregulation of EZH1 and EZH2 in Tregs, the expression of KDM6A/UTX and KDM6B/JMJD3, which catalyze H3K27 demethylation (Shi, 2007), is also elevated (Figure S3C).”
InfluentialContinuous immunotypes describe human immune variation and predict diverse responses
Kaczorowski, K. J., Shekhar, K., Nkulikiyimfura, D., Dekker, C. L., Maecker, H. T., Davis, M. M., Chakraborty, A. K., & Brodin, P. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705065114 · Cited by 136 · cited 2× · see citing works
“Recent publications have described increased variability in the immune systems of older versus younger human beings (Brodin and Davis, 2017; Kaczorowski et al., 2017).”
Self-citationEpigenetic inheritance: uncontested
Zhu, B., & Reinberg, D. (2011) · Cell Research · doi:10.1038/cr.2011.26 · Cited by 100 · cited 1× · see citing works
“This hypothesis helps explain our results on chromatin modifications in twins; however, a unified mechanism for the patterns of chromatin modifications to be reestablished during mitotic cell division remains unclear (Zhu and Reinberg, 2011).”
mixtools: An R Package for Analyzing Finite Mixture Models
Benaglia, T., Chauveau, D., Hunter, D. R., & Young, D. S. (2009) · Cited by 99 · see citing works
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Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans
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Self-citationDNA methylation aging clocks: challenges and recommendations
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Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
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BackgroundEpigenetic regulation of aging: implications for interventions of aging and diseases
Kang, W., Liu, H., Hu, Q., Wang, L., Liu, J., Zheng, Z., Zhang, W., Ren, J., Zhu, F., & Liu, G. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01211-8 · Cited by 694 · see citing works
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Characterizing mutagenic effects of recombination through a sequence-level genetic map
Halldórsson, B. V., Pálsson, G., Stefánsson, Ó. A., Jónsson, H., Hardarson, M. T., Eggertsson, H. P., Gunnarsson, B., Oddsson, Á., Halldorsson, G. H., Zink, F., et al. (2019) · Science · doi:10.1126/science.aau1043 · Cited by 364 · see citing works
“It is conceivable that age-related loss of epigenomic integrity (87) is more pronounced in late-replicating regions.”
BackgroundElyahu, Y., Hekselman, I., Eizenberg-Magar, I., Berner, O., Strominger, I., Schiller, M., Mittal, K., Nemirovsky, A., Eremenko, E., Vital, A., et al. (2019) · Science Advances · doi:10.1126/sciadv.aaw8330 · Cited by 324 · see citing works
“In line with these findings, increased variation of chromatin modifications was recently observed in immune cells from elderly individuals (18).”
BackgroundHuman bone marrow assessment by single-cell RNA sequencing, mass cytometry, and flow cytometry
Oetjen, K. A., Lindblad, K. E., Goswami, M., Gui, G., Dagur, P. K., Lai, C., Dillon, L. W., McCoy, J. P., & Hourigan, C. S. (2018) · JCI Insight · doi:10.1172/jci.insight.124928 · Cited by 272 · see citing works
The epigenetic basis of cellular heterogeneity
Carter, B. C., & Zhao, K. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-020-00300-0 · Cited by 314 · see citing works
Epigenetic changes during aging and their reprogramming potential
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“A recent single cell analysis of human peripheral blood mononuclear cells detected cell type-specific changes to histone modifications during aging, with an overall increased heterogeneity between both cells and individuals (Cheung et al. 2018).”
BackgroundMethodChallenges in measuring and understanding biological noise
Eling, N., Morgan, M. D., & Marioni, J. C. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0130-6 · Cited by 247 · see citing works
A human circulating immune cell landscape in aging and COVID-19
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“For humans, mass cytometry analysis showed that aging increased epigenetic variations in circulatory immune cells (Cheung et al., 2018).”
BackgroundHeterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing
Mahmoudi, S., Mancini, E., Xu, L., Moore, A., Jahanbani, F., Hebestreit, K., Srinivasan, R., Li, X., Devarajan, K., Prélot, L., et al. (2019) · Nature · doi:10.1038/s41586-019-1658-5 · Cited by 285 · see citing works
The single-cell epigenomic and transcriptional landscape of immunity to influenza vaccination
Wimmers, F., Donato, M., Kuo, A. J., Ashuach, T., Gupta, S., Li, C., Dvorak, M., Foecke, M. H., Chang, S. E., Hagan, T., et al. (2021) · Cell · doi:10.1016/j.cell.2021.05.039 · Cited by 264 · see citing works
Self-citationCellular and epigenetic drivers of stem cell ageing
Ermolaeva, M., Neri, F., Ori, A., & Rudolph, K. L. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0020-3 · Cited by 272 · see citing works
The science and medicine of human immunology
Pulendran, B., & Davis, M. M. (2020) · Science · doi:10.1126/science.aay4014 · Cited by 276 · see citing works
“Single-cell mass cytometry techniques allow analysis of the cellular dynamics of immune responses with an exquisite degree of precision (36) and analysis of the epigenetic landscape of single cells (37) (Fig.”
Self-citationHernando-Herraez, I., Evano, B., Stubbs, T., Commere, P.-H., Jan Bonder, M., Clark, S., Andrews, S., Tajbakhsh, S., & Reik, W. (2019) · Nature Communications · doi:10.1038/s41467-019-12293-4 · Cited by 236 · see citing works
Peripheral immune system in aging and Alzheimer’s disease
Cao, W., & Zheng, H. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0284-2 · Cited by 214 · see citing works
FOXO transcription factors as mediators of stress adaptation
Colman, M. J. R., Dansen, T. B., & Burgering, B. M. T. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00649-0 · Cited by 225 · see citing works
“…the epigenetic landscape changes, for example, as observed during stem cell differentiation, cancer development (discussed subsequently) and ageing 76 (reviewed elsewhere 77,78 ), this may result in a changing landscape of enhancer activity and thus may have a profound impact on the set of genes…”
Adelman, E. R., Huang, H.-T., Roisman, A., Olsson, A., Colaprico, A., Qin, T., Lindsley, R. C., Bejar, R. L., Salomonis, N., Grimes, H. L., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1474 · Cited by 222 · see citing works
“Because we also observed gene-expression alterations in KAT5/7/8, KDM2A/3A, SETD6/8, and HDAC11, it is possible that HSCe aging may also present focal alterations in other histone modifications, as has been observed at the global level by others (25).”
BackgroundBone Aging, Cellular Senescence, and Osteoporosis
Pignolo, R. J., Law, S. F., & Chandra, A. (2021) · JBMR Plus · doi:10.1002/jbm4.10488 · Cited by 206 · see citing works
Single-cell analyses of aging, inflammation and senescence
Uyar, B., Palmer, D. H., Kowald, A., Escobar, H. M., Barrantes, I., Möller, S., Akalin, A., & Fuellen, G. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101156 · Cited by 202 · see citing works
Immune monitoring using mass cytometry and related high-dimensional imaging approaches
Hartmann, F. J., & Bendall, S. C. (2019) · Nature Reviews Rheumatology · doi:10.1038/s41584-019-0338-z · Cited by 203 · see citing works
Biohorology and biomarkers of aging: Current state-of-the-art, challenges and opportunities
Galkin, F., Mamoshina, P., Aliper, A., de Magalhães, J. P., Gladyshev, V. N., & Zhavoronkov, A. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101050 · Cited by 189 · see citing works
Understanding intrinsic hematopoietic stem cell aging
Mejía-Ramírez, E., & Florian, M. C. (2019) · Haematologica · doi:10.3324/haematol.2018.211342 · Cited by 191 · see citing works
Human immune diversity: from evolution to modernity
Liston, A., Humblet-Baron, S., Duffy, D., & Goris, A. (2021) · Nature Immunology · doi:10.1038/s41590-021-01058-1 · Cited by 187 · see citing works
Sex Hormones Regulate Innate Immune Cells and Promote Sex Differences in Respiratory Virus Infection
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Hallmarks of the aging T‐cell system
Zhang, H., Weyand, C. M., & Goronzy, J. J. (2021) · FEBS Journal · doi:10.1111/febs.15770 · Cited by 177 · see citing works
Aging and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?
Mayne, K., White, J. A., McMurran, C. E., Rivera, F. J., & de la Fuente, A. G. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.572090 · Cited by 167 · see citing works
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WTAP-mediated m6A modification of lncRNA NORAD promotes intervertebral disc degeneration
Li, G., Ma, L., He, S., Luo, R., Wang, B., Zhang, W., Song, Y., Liao, Z., Ke, W., Xiang, Q., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28990-6 · Cited by 155 · see citing works
Genetic and epigenetic regulation of human aging and longevity
Morris, B. J., Willcox, B. J., & Donlon, T. A. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.08.039 · Cited by 140 · see citing works
Epigenetic mechanisms regulating T-cell responses
Schmidl, C., Delacher, M., Huehn, J., & Feuerer, M. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.07.014 · Cited by 144 · see citing works
Methylation across the central dogma in health and diseases: new therapeutic strategies
Liu, R., Zhao, E., Yu, H., Yuan, C., Abbas, M. N., & Cui, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01528-y · Cited by 147 · see citing works
Brain macrophage development, diversity and dysregulation in health and disease
Silvin, A., Qian, J., & Ginhoux, F. (2023) · Cellular & Molecular Immunology · doi:10.1038/s41423-023-01053-6 · Cited by 137 · see citing works
“Studies have already shown that aging monocytes display epigenetic alterations, particularly at the level of H3K27M [70], and clonal mutations of key genes such as TET2 or DNMT3A greatly impact myelopoiesis, as shown by Lim et al. or Assmus et al. [71, 72].”
BackgroundNew Insights into the Role of Histone Changes in Aging
Yi, S.-J., & Kim, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218241 · Cited by 133 · see citing works
Single-cell omics in ageing: a young and growing field
He, X., Memczak, S., Qu, J. T., Belmonte, J. C. I., & Liu, G. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0196-7 · Cited by 128 · see citing works
Levine, L. S., Hiam-Galvez, K. J., Marquez, D. M., Tenvooren, I., Madden, M. Z., Contreras, D. C., Dahunsi, D. O., Irish, J. M., Oluwole, O. O., Rathmell, J. C., et al. (2020) · Immunity · doi:10.1016/j.immuni.2021.02.018 · Cited by 128 · see citing works
“This approach has permitted characterization of various aspects of cellular behavior including phenotype, signaling (Bodenmiller et al., 2012), proliferation (Good et al., 2019) and chromatin state (Cheung et al., 2018).”
BackgroundPhysiology and pathology of T-cell aging
Minato, N., Hattori, M., & Hamazaki, Y. (2020) · International Immunology · doi:10.1093/intimm/dxaa006 · Cited by 121 · see citing works
Mechanisms and rejuvenation strategies for aged hematopoietic stem cells
Li, X., Zeng, X., Xu, Y., Wang, B., Zhao, Y., Lai, X., Qian, P., & Huang, H. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00864-8 · Cited by 118 · see citing works
Scriba, T. J., Netea, M. G., & Ginsberg, A. M. (2020) · Seminars in Immunology · doi:10.1016/j.smim.2020.101431 · Cited by 110 · see citing works
Genomic Instability and Epigenetic Changes during Aging
López-Gil, L., Pascual‐Ahuir, A., & Proft, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241814279 · Cited by 120 · see citing works
A stem cell aging framework, from mechanisms to interventions
Liu, B., Qu, J. T., Zhang, W., Belmonte, J. C. I., & Liu, G. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111451 · Cited by 107 · see citing works
Advanced model systems and tools for basic and translational human immunology
Wagar, L. E., DiFazio, R. M., & Davis, M. M. (2018) · Genome Medicine · doi:10.1186/s13073-018-0584-8 · Cited by 102 · see citing works
Self-citationPrinciples of the Molecular and Cellular Mechanisms of Aging
da Silva, P. F. L., & Schumacher, B. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2020.11.018 · Cited by 99 · see citing works
Stress, diet, exercise: Common environmental factors and their impact on epigenetic age
Galkin, F., Kovalchuk, O., Koldasbayeva, D., Zhavoronkov, A. A., & Bischof, E. Y. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101956 · Cited by 107 · see citing works
“Influence of the environmental factors was best determined so far in twin studies, some of which reported 70–80% of epigenetic variance to be attributed to external influences(Cheung et al., 2018; van Dongen et al., 2016).”
BackgroundResultChannappanavar, R., & Perlman, S. M. (2020) · Journal of Clinical Investigation · doi:10.1172/jci144115 · Cited by 92 · see citing works
“Analyses of peripheral blood cells from naive young and aged individuals using multiple omics technologies demonstrated (a) polarization of immune cells toward an inflammatory phenotype, (b) reduced T and B cell receptor diversity and increased clonal expansion, and (c) accumulation of myeloid cell populations with ad…”
MethodElyahu, Y., & Monsonego, A. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101231 · Cited by 91 · see citing works
“, memory T cells and NK cells) of elderly individuals (Cheung et al., 2018).”
Mancarella, D., & Plass, C. (2021) · Genome Medicine · doi:10.1186/s13073-021-00837-7 · Cited by 91 · see citing works
“Increased age was also positively correlated with an increased instability of the chromatin state and hence, an increased heterogeneity of chromatin modifications was observed between older individuals in a twin study [5].”
BackgroundCheung, P., Schaffert, S. A., Chang, S. E., Dvorak, M., Donato, M., Macaubas, C., Foecke, M. H., Li, T., Zhang, L., Coan, J. P., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-00928-y · Cited by 88 · see citing works
“Epigenetic landscape profiling using cytometry by Time-Of-Flight (EpiTOF) 12 analysis revealed cell type-specific enrichment of proteolytically processed histone H3 cleaved between amino acids alanine 21 and threonine 22 (H3ΔNThr22) in HLA-DR + CD33 + CD14 + monocytes (Fig.”
Self-citationTissue-specific impacts of aging and genetics on gene expression patterns in humans
Yamamoto, R., Chung, R., Vázquez, J. M., Sheng, H., Steinberg, P. L., Ioannidis, N. M., & Sudmant, P. H. (2022) · Nature Communications · doi:10.1038/s41467-022-33509-0 · Cited by 79 · see citing works
Epigenomic drivers of immune dysfunction in aging
Keenan, C. R., & Allan, R. S. (2018) · Aging Cell · doi:10.1111/acel.12878 · Cited by 76 · see citing works
“…used a single cell mass cytometry approach to provide the first insight of the effect of aging on 40 of these marks in different human immune cell populations, revealing more variation in chromatin modification profiles in older individuals compared to younger individuals (Cheung et al., 2018).”
BackgroundA guide to systems-level immunomics
Bonaguro, L., Schulte-Schrepping, J., Ulas, T., Aschenbrenner, A. C., Beyer, M., & Schultze, J. L. (2022) · Nature Immunology · doi:10.1038/s41590-022-01309-9 · Cited by 74 · see citing works
Cell engineering: Biophysical regulation of the nucleus
Song, Y., Soto, J., Chen, B., Yang, L., & Li, S. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2019.119743 · Cited by 68 · see citing works
- Retracted
ASXL1 mutation in clonal hematopoiesis
Fujino, T., & Kitamura, T. (2020) · Experimental Hematology · doi:10.1016/j.exphem.2020.01.002 · Cited by 61 · see citing works
Advances and novel developments in environmental influences on the development of atopic diseases
Alkotob, S., Cannedy, C., Harter, K., Movassagh, H., Paudel, B., Prunicki, M. M., Sampath, V., Schikowski, T., Smith, E. M., Zhao, Q., et al. (2020) · Allergy · doi:10.1111/all.14624 · Cited by 61 · see citing works
Progress and applications of mass cytometry in sketching immune landscapes
Zhang, T., Warden, A. R., Li, Y., & Ding, X. (2020) · Clinical and Translational Medicine · doi:10.1002/ctm2.206 · Cited by 62 · see citing works
Vries, N. L. D., Mahfouz, A. E., Koning, F., & de Miranda, N. F. C. C. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01254 · Cited by 58 · see citing works
“Interestingly, variability in histone modification patterns in single cells have also been studied by mass cytometry, which was denominated EpiTOF (94).”
BackgroundVascular Calcification in Chronic Kidney Disease: An Update and Perspective
Ren, S., Mao, N., Si, Y., Ma, X., Zou, J., Tang, X., & Fan, J. (2022) · Aging and Disease · doi:10.14336/ad.2021.1024 · Cited by 60 · see citing works
“Studies have shown that aging and VC processes are regulated by epigenetic modification, including microRNAs and histone posttranslational modulators [232, 233].”
BackgroundKörholz, J., Zocher, S., Grzyb, A. N., Morisse, B., Poetzsch, A., Ehret, F., Schmied, C., & Kempermann, G. (2018) · eLife · doi:10.7554/elife.35690 · Cited by 58 · see citing works
“…brain areas (Diamond, Johnson, Protti, & Ott, 1985; Diamond, Krech, & Rosenzweig, 1964; Diamond et al., 1966), and different behavioral aspects (Clemenson et al., 2015; Garthe, Roeder, & Kempermann, 2015), it was of particular interest to test the ENR effect on the variance of these parameters.”
Single-cell epigenetic analysis reveals principles of chromatin states in H3.3-K27M gliomas
Harpaz, N., Mittelman, T., Beresh, O., Griess, O., Furth, N., Salame, T., Oren, R., Fellus‐Alyagor, L., Harmelin, A., Alexandrescu, S., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.05.023 · Cited by 56 · see citing works
Vendrov, A. E., Lozhkin, A. P., Hayami, T., Levin, J., Chamon, J. S. F., Abdel‐Latif, A., Runge, M. S., & Madamanchi, N. R. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1410832 · Cited by 58 · see citing works
Probing infectious disease by single-cell RNA sequencing: Progresses and perspectives
Luo, G., Gao, Q., Zhang, S., & Yan, B. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.10.016 · Cited by 59 · see citing works
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 61 · see citing works
“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 · see citing works
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 56 · see citing works
Galow, A.-M., & Peleg, S. (2022) · Cells · doi:10.3390/cells11030468 · Cited by 58 · see citing works
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 · see citing works
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 54 · see citing works
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 · see citing works
Mapping chromatin modifications at the single cell level
Ludwig, C., & Bintu, L. (2019) · Development · doi:10.1242/dev.170217 · Cited by 53 · see citing works
“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 52 · see citing works
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 51 · see citing works
“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 50 · see citing works
“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 50 · see citing works
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 48 · see citing works
“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 47 · see citing works
Immune Memory in Aging: a Wide Perspective Covering Microbiota, Brain, Metabolism, and Epigenetics
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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 · see citing works
“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 45 · see citing works
“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 · see citing works
“…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.”
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Single Cell Omics: From Assay Design to Biomedical Application
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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 · see citing works
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 42 · see citing works
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 44 · see citing works
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 38 · see citing works
Self-citationInfluence of human gut microbiome on the healthy and the neurodegenerative aging
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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 44 · see citing works
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 39 · see citing works
“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 42 · see citing works
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 36 · see citing works
“…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
- 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 · 2017: 1
- 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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