The chromatin accessibility signature of human immune aging stems from CD8+ T cells

Ucar, Duygu; Márquez, Eladio J.; Chung, Ching‐Hu; Marcheş, Radu; Rossi, Robert J.; Uyar, Asli; Wu, Te-Chia; George, Joshy; Stitzel, Michael L.; Palucka, A. Karolina; Kuchel, George A.; Banchereau, Jacques

doi:10.1084/jem.20170416

Cited by 153 publications

(184 citation statements)

References 81 publications

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“…80 the age-associated differentiation is a feature of CD8 T cells and much less prominent in CD4 T cells. 50 In conclusion, T cell aging involves gene regulatory pathways that drive T cell differentiation and the increased susceptibility of CD8 T cells to age-associated changes appears to be a heightened inducibility of these pathways (Fig. 3).…”

Section: Epigenetic Signatures Of Cellular Differentiation In Cd8 T Cmentioning

confidence: 84%

“…Moreover, using ATAC‐seq, Ucar et al. found significant chromatin closing with aging of several histone genes ( HIST1H3D , HIST1H3E , and HIST4H4 ) consistent with the reduced expression of core histones in model systems of aging …”

Section: Introductionmentioning

confidence: 94%

“…Studies by Ucar et al., mostly on unfractionated peripheral blood mononuclear cells, revealed a systematic loss of chromatin accessibility at the promoters and enhancers of immune module genes and a gain in accessibility in the vicinity of genes that in the ENCODE data base are described as generally repressed or quiescent. Moreover, genes for several histone modifiers (EZH1, SETD7) were found to be less accessible that cause histone modification patterns similar to those seen with cellular aging …”

Section: Introductionmentioning

confidence: 99%

“…The technique has been successfully applied by us and others to define the epigenetic landscape of antigen‐specific CD8 T cells as they differentiate from naïve T cells into functional effector and memory cells . Two manuscripts have been recently published that used this technique to describe how the epigenetic landscapes of T cells change with aging and whether these changes allow conclusions on the mechanisms and regulatory transcription factor networks involved . Ucar and colleagues compared chromatin accessibility maps in PBMC of twenty‐eight 22 to 40‐year‐old healthy individuals and 21 individuals older than 65 years and identified 12,626 differentially accessible sites (9% of those tested) with approximately an equal number of sites opening or closing with age.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetics of T cell aging

Goronzy

Kim

et al. 2018

Journal of Leukocyte Biology

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T cells are a heterogeneous population of cells that differ in their differentiation stages. Functional states are reflected in the epigenome that confers stability in cellular identity and is therefore important for naïve as well as memory T cell function. In many cellular systems, changes in chromatin structure due to alterations in histone expression, histone modifications and DNA methylation are characteristic of the aging process and cause or at least contribute to cellular dysfunction in senescence. Here, we review the epigenetic changes in T cells that occur with age and discuss them in the context of canonical epigenetic marks in aging model systems as well as recent findings of chromatin accessibility changes in T cell differentiation. Remarkably, transcription factor networks driving T cell differentiation account for many of the age-associated modifications in chromatin structures suggesting that loss of quiescence and activation of differentiation pathways are major components of T cell aging.

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Section: Epigenetic Signatures Of Cellular Differentiation In Cd8 T Cmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigenetics of T cell aging

Goronzy

Kim

et al. 2018

Journal of Leukocyte Biology

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“…It is also unclear to what extent one is the cause and the other is the effect, or indeed whether their relationship is reciprocal. Epigenetics are not limited to DNA methylation and also include histone modification and higher-order changes to chromatin structure and nuclear architecture[44]. Indeed, nuclear-architecture-associated proteins such as CTCF likely reinforce these initial methylation changes[45].…”

Section: Metastability Of Aging Phenotypesmentioning

confidence: 99%

Tissue aging: the integration of collective and variant responses of cells to entropic forces over time

Todhunter

Sayaman

Miyano

et al. 2018

Current Opinion in Cell Biology

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Aging is driven by unavoidable entropic forces, physicochemical in nature, that damage the raw materials that constitute biological systems. Single cells experience and respond to stochastic physicochemical insults that occur either to the cells themselves or to their microenvironment, in a dynamic and reciprocal manner, leading to increased age-related cell-to-cell variation. We will discuss the biological mechanisms that integrate cell-to-cell variation across tissues resulting in stereotypical phenotypes of age.

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Genome‐Wide Reduction in Chromatin Accessibility and Unique Transcription Factor Footprints in Endothelial Cells and Fibroblasts in Scleroderma Skin

Tsou

Palisoc

Ali

et al. 2021

Arthritis & Rheumatology

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Objective. Systemic sclerosis (SSc) is characterized by widespread fibrosis and vascular complications. This study was undertaken to examine the chromatin landscape and transcription factor footprints in SSc, using an assay for genome-wide chromatin accessibility.Methods. Dermal endothelial cells (ECs) and fibroblasts were isolated from healthy controls and patients with diffuse cutaneous SSc (dcSSc). Assay for transposase-accessible chromatin with sequencing (ATAC-seq) was performed to assess genome-wide chromatin accessibility at a read depth of ~150 million reads per sample. Transcription factor footprinting and motif binding analysis were performed, followed by functional experiments.Results. Chromatin accessibility was significantly reduced in dcSSc patients compared to healthy controls. Differentially accessible chromatin loci were enriched in pathways and gene ontologies involved in the nervous system, cell membrane projections and cilia motility, nuclear and steroid receptors, and nitric oxide. In addition, chromatin binding of transcription factors SNAI2, ETV2, and ELF1 was significantly increased in dcSSc ECs, while recruitment of RUNX1 and RUNX2 was enriched in dcSSc fibroblasts. We found significant down-regulation of the neuronal gene NRXN1 and up-regulation of SNAI2 and ETV2 in dcSSc ECs. In dcSSc fibroblasts, down-regulation of the neuronal gene ENTPD1 and up-regulation of RUNX2 were confirmed. Further functional analysis revealed that ETV2 and NRXN1 dysregulation affected angiogenesis in ECs, while ENTPD1 enhanced profibrotic properties in dcSSc fibroblasts. Conclusion.Our data identify the chromatin blueprint of dcSSc, and suggest that neuronal-related characteristics of SSc ECs and fibroblasts could be a culprit for dysregulated angiogenesis and enhanced fibrosis. Targeting the key pathways and transcription factors identified might present novel therapeutic approaches in SSc.

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The chromatin accessibility signature of human immune aging stems from CD8+ T cells

Abstract: Ucar et al. describe a novel chromatin accessibility signature of aging that is borne by memory CD8+ T cells but is detectable from PBMCs. This signature harbors the IL7R gene as a potential biomarker of aging-associated immunodeficiency.

Cited by 153 publications

References 81 publications

Epigenetics of T cell aging

Epigenetics of T cell aging

Tissue aging: the integration of collective and variant responses of cells to entropic forces over time

Genome‐Wide Reduction in Chromatin Accessibility and Unique Transcription Factor Footprints in Endothelial Cells and Fibroblasts in Scleroderma Skin

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