Chromatin repression by PRC2 results in reduced gene expression driving key features of CD8 T cell exhaustion [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE263885 | GEO | 2024/10/31
REPOSITORIES: GEO
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Project description:Exhausted CD8 T cells result from chronic antigen stimulation and have reduced ability to clear disease. The epigenetic regulation of the dysfunctional phenotype of exhausted CD8 T cells is a promising avenue for therapies aimed at reversing or preventing CD8 T cell exhaustion. Here, utilizing an in vitro model, we show global increase of the repressive histone modification H3K27me3 in CD8 T cell exhaustion as well as increased gene expression of the subunits of PRC2, the complex responsible for H3K27me3 deposition. H3K27me3 correlated with decreased gene expression and localized to naïve/memory T cell genes in CD8 T cell exhaustion. PRC2 inhibition increased expression of many of these naïve/memory genes while reducing expression of key exhaustion genes. Further, we identified potential enhancers and transcription factors predicted to promote expression of the PRC2 subunits. Our study highlights the importance of the repressive epigenetic landscape of exhausted CD8 T cells as well as a novel role for PRC2 in T cell biology.
2024-10-31 | GSE263937 | GEO
Project description:Histone methylations play a major role in regulating the chromatin state and gene expression, yet little is known about their involvement in differential gene expression and function of memory CD8 T cells. Here, we report a genome-wide analysis of two histone H3 methylations (H3K4me3 and H3K27me3) and gene expression in naïve, central (TCM) and effector (TEM) memory CD8 T cells. Analysis of 16,314 annotated genes in CD8 T cell subsets revealed that gene expression were positively correlated with the levels of H3K4me3 and negatively correlated with the levels of H3K27me3 in these gene loci. The correlation between differential H3K4me3 orH3K27me3 levels with gene expressions in memory CD8 T cells displayed four distinct modes: repressive, active, poised, and bivalent, reflecting their complex regulation and different function of these genes. Furthermore, accessible chromatin states of different gene loci were preferentially influenced by different histone modifications as demonstrated here high levels of H3K9ac found in active gene loci without high levels of H3K4me3. These findings reveal a histone methylation based complex regulation of differential gene expression in memory CD8 T cells. Thus, change of chromatin structure mediated by histone methylation may serve a fundamental basis for the rapid transcriptional response of memory CD8 T cells. genome-wide analysis of two histone H3 methylations (H3K4me3 and H3K27me3) in naïve, central (TCM) and effector (TEM) memory CD8 T cells.
2009-06-12 | E-GEOD-12616 | biostudies-arrayexpress
Project description:Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. CD8+ T cells from subjects with HCV infection were sorted and pelleted and re-suspended in TRIzol (Invitrogen). RNA extraction was performed using the RNAdvance Tissue Isolation kit (Agencourt). Concentrations of total RNA were determined with a Nanodrop spectrophotometer or Ribogreen RNA quantification kits (Molecular Probes/Invitrogen). RNA purity was determined by Bioanalyzer 2100 traces (Agilent Technologies). Total RNA was amplified with the WT-Ovation Pico RNA Amplification system (NuGEN) according to the manufacturer's instructions. After fragmentation and biotinylation, cDNA was hybridized to HG-U133A 2.0 microarrays (Affymetrix).
2015-09-08 | E-GEOD-72752 | biostudies-arrayexpress
Project description:Histone methylations play a major role in regulating the chromatin state and gene expression, yet little is known about their involvement in differential gene expression and function of memory CD8 T cells. Here, we report a genome-wide analysis of two histone H3 methylations (H3K4me3 and H3K27me3) and gene expression in naïve, central (TCM) and effector (TEM) memory CD8 T cells. Analysis of 16,314 annotated genes in CD8 T cell subsets revealed that gene expression were positively correlated with the levels of H3K4me3 and negatively correlated with the levels of H3K27me3 in these gene loci. The correlation between differential H3K4me3 orH3K27me3 levels with gene expressions in memory CD8 T cells displayed four distinct modes: repressive, active, poised, and bivalent, reflecting their complex regulation and different function of these genes. Furthermore, accessible chromatin states of different gene loci were preferentially influenced by different histone modifications as demonstrated here high levels of H3K9ac found in active gene loci without high levels of H3K4me3. These findings reveal a histone methylation based complex regulation of differential gene expression in memory CD8 T cells. Thus, change of chromatin structure mediated by histone methylation may serve a fundamental basis for the rapid transcriptional response of memory CD8 T cells. Keywords: Histone methylations, chromatin state, CD8 memory T cells Enriched naïve and memory CD8 T cells were purified into CD8+CD45RA+CD62L+ naïve T cells, CD8+CD45RA-CD62L+ central memory T cells (TCM), and CD8+CD45RA-CD62L- effector memory T cells (TEM) by a cell sorter (MoFlo; Dako Cytomation, Carpentaria, CA). Triplicates of each cell type were either used right away or incubated with anti-CD3 and anti-CD28 Ab (anti-CD3/CD28) coupled magnetic beads (Invitrogen) at the cell:bead ratio of 1:1 for 16 hours in RPMI-1640 with 10% Fetal bovine serum and penicillin (10 U/ml)/streptomycin (10 ug/ml) (Invitrogen). The freshly isolated and 16 hr stimulated cells from several donors as a pool were used for gene expression microarray analysis. All sample data was normalized to a standard control RNA labeled and hybed along with each sample and all data from the 3 replicates was averaged.
2009-03-06 | E-GEOD-14422 | biostudies-arrayexpress
Project description:During acute viral infections, naïve CD8+ T cells differentiate into effector CD8+ T cells and, after viral control, into memory CD8+ T cells. Memory CD8+ T cells are highly functional, proliferate rapidly upon reinfection and persist long-term without antigen. In contrast, during chronic infections, CD8+ T cells become “exhausted” and have poor effector function, express multiple inhibitory receptors, possess low proliferative capacity, and cannot persist without antigen. To compare the development of functional memory T cells with poorly functional exhausted T cells, we generated longitudinal transcriptional profiles for each. Naive CD44Lo CD8+ T cells were isolated and sorted from uninfected C57BL/6 mice and H2-Db GP33-specific CD8+ T cells were sorted using MHC-I tetramers at d6, 8, 15, and 30 p.i. with either LCMV Arm or LCMV clone 13. RNA from these CD8+ T cells was processed, amplified, labeled, and hybridized to Affymetrix GeneChip MoGene 1.0 st microarrays
2012-11-23 | E-GEOD-41867 | biostudies-arrayexpress
Project description:Chronic hepatitis C virus (HCV) infection is associated with CD8+ T-cell exhaustion characterized by limited effector functions and thus compromised anti-viral activity. Exhausted HCV-specific CD8+ T cells are comprised of memory-like and terminally exhausted CD8+ T-cell subsets. So far, little is not known about the molecular profile and fate of these cells after elimination of chronic antigen stimulation by direct acting antiviral therapy (DAA). Here, we report an antigen-driven molecular core signature underlying exhausted CD8+ T-cell subset heterogeneity in chronic viral infection with a progenitor/progeny relationship of memory-like and terminally exhausted HCV-specific CD8+ T cells via an intermediate stage. Furthermore, transcriptional profiling reveals that the memory-like cells remain after DAA-mediated cure while terminally exhausted HCV-specific CD8+ T-cell subsets are lost. Thus, the memory polarization of the overall HCV-specific CD8+ T-cell response after cure does not result from re-differentiation of exhausted T cells. Consequently, antigen elimination has little impact on the exhausted core signature of memory-like CD8+ T cells that remains clearly different from bona fide T-cell memory. These results identify a molecular signature of T-cell exhaustion that is imprinted like a chronic scar in HCV-specific CD8+ T cells even after HCV cure, highlighting the requirement of re-programming to elicit full effector potential of exhausted T cells.
| EGAD00001006259 | EGA
Project description:Chronic hepatitis C virus (HCV) infection is associated with CD8+ T-cell exhaustion characterized by limited effector functions and thus compromised anti-viral activity. Exhausted HCV-specific CD8+ T cells are comprised of memory-like and terminally exhausted CD8+ T-cell subsets. So far, little is not known about the molecular profile and fate of these cells after elimination of chronic antigen stimulation by direct acting antiviral therapy (DAA). Here, we report an antigen-driven molecular core signature underlying exhausted CD8+ T-cell subset heterogeneity in chronic viral infection with a progenitor/progeny relationship of memory-like and terminally exhausted HCV-specific CD8+ T cells via an intermediate stage. Furthermore, transcriptional profiling reveals that the memory-like cells remain after DAA-mediated cure while terminally exhausted HCV-specific CD8+ T-cell subsets are lost. Thus, the memory polarization of the overall HCV-specific CD8+ T-cell response after cure does not result from re-differentiation of exhausted T cells. Consequently, antigen elimination has little impact on the exhausted core signature of memory-like CD8+ T cells that remains clearly different from bona fide T-cell memory. These results identify a molecular signature of T-cell exhaustion that is imprinted like a chronic scar in HCV-specific CD8+ T cells even after HCV cure, highlighting the requirement of re-programming to elicit full effector potential of exhausted T cells.
| EGAS00001004538 | EGA
Project description:CD8 T cells normally differentiate from resting naïve T cells into function effector and then memory CD8 T cells following acute infections. During chronic viral infections, however, virus-specific CD8 T cells often become exhausted. We used microarrays to examine the gene expression differences between naive, effector, memory and exhausted virus-specific CD8 T cells following lymphocytic choriomeningitis virus infection. Experiment Overall Design: Three or four independent samples were sorted by flow cytometry for each cell type (naive, effector, memory and exhausted) virus-specific CD8 T cells. RNA was extracted and hybridized to Affymetrix microarrays.
2008-06-16 | E-GEOD-9650 | biostudies-arrayexpress
Project description:The first lineage choice made in human embryo development separates trophectoderm from the inner cell mass, which proceeds to form the pluripotent epiblast and primitive endoderm. Trophectoderm on the other hand gives rise to the placenta. Naïve pluripotent stem cells are derived from the pluripotent epiblast of the blastocyst and offer possibilities to explore how lineage integrity is maintained. Here, we discover that Polycomb repressive complex 2 (PRC2) restricts an intrinsic capacity of naïve pluripotent stem cells to give rise to trophectoderm. Through quantitative epigenome profiling, we find that broad histone H3 lysine 27 trimethylation (H3K27me3) hypermethylation is a common feature of naïve pluripotency across species. We define a previously unappreciated, naïve-specific set of bivalent promoters, featuring PRC2-mediated H3K27me3 concomitant with H3K4me3. Naïve bivalency maintains key trophectoderm transcription factors in a transcriptionally poised state that is resolved to an active state upon depletion of H3K27me3 via inhibition of the enzymatic subunits of PRC2, EZH1/2. Conversely, primed human embryonic stem cells cannot be driven towards trophectoderm development via PRC2 inhibition. While naïve and primed hESCs share the majority of bivalent promoters, PRC2 contributes to the repression of largely non-overlapping subsets of these promoters in each state, hence H3K27me3-mediated repression provides a highly adaptive mechanism to restrict lineage potential during early human development.
2021-08-23 | GSE181242 | GEO
Project description:The first lineage choice made in human embryo development separates trophectoderm from the inner cell mass, which proceeds to form the pluripotent epiblast and primitive endoderm. Trophectoderm on the other hand gives rise to the placenta. Naïve pluripotent stem cells are derived from the pluripotent epiblast of the blastocyst and offer possibilities to explore how lineage integrity is maintained. Here, we discover that Polycomb repressive complex 2 (PRC2) restricts an intrinsic capacity of naïve pluripotent stem cells to give rise to trophectoderm. Through quantitative epigenome profiling, we find that broad histone H3 lysine 27 trimethylation (H3K27me3) hypermethylation is a common feature of naïve pluripotency across species. We define a previously unappreciated, naïve-specific set of bivalent promoters, featuring PRC2-mediated H3K27me3 concomitant with H3K4me3. Naïve bivalency maintains key trophectoderm transcription factors in a transcriptionally poised state that is resolved to an active state upon depletion of H3K27me3 via inhibition of the enzymatic subunits of PRC2, EZH1/2. Conversely, primed human embryonic stem cells cannot be driven towards trophectoderm development via PRC2 inhibition. While naïve and primed hESCs share the majority of bivalent promoters, PRC2 contributes to the repression of largely non-overlapping subsets of these promoters in each state, hence H3K27me3-mediated repression provides a highly adaptive mechanism to restrict lineage potential during early human development.
2021-08-23 | GSE181241 | GEO