Promoter H3K4 methylation dynamically reinforces activation-induced pathways in human CD4 T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE73214 | GEO | 2016/06/01
SECONDARY ACCESSION(S): PRJNA296378
REPOSITORIES: GEO
Similar Datasets
Project description:The epigenetic determinants driving the responses of CD4 T cells to antigen are currently an area of active research. Much has been done to characterize helper T-cell subsets and their associated genome-wide epigenetic patterns. In contrast, little is known about the dynamics of histone modifications during CD4 T-cell activation and the differential kinetics of these epigenetic marks between naive and memory T cells. In this study, we have detailed the dynamics of genome-wide promoter H3K4me2 and H3K4me3 over a time course during activation of human naive and memory CD4 T cells. Our results demonstrate that changes to H3K4 methylation occur relatively late after activation (5 days) and reinforce activation-induced upregulation of gene expression, affecting multiple pathways important to T-cell activation, differentiation and function. The dynamics and mapped pathways of H3K4 methylation are distinctly different in memory cells, which have substantially more promoters marked by H3K4me3 alone, reinforcing their more differentiated state. Our study provides the first data examining genome-wide histone modification dynamics during CD4 T-cell activation, providing insight into the cross talk between H3K4 methylation and gene expression, and underscoring the impact of these marks upon key pathways integral to CD4 T-cell activation and function.
| S-EPMC4956548 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-06-01 | E-GEOD-73214 | biostudies-arrayexpress
Project description:The epigenetic determinants driving the rapid responses of memory CD4 T cells to antigen are currently an area of active research. While much has been done to characterize various Th subsets and their associated genome-wide epigenetic patterns, the dynamics of histone modifications during CD4 T cell activation and the differential kinetics of these epigenetic marks between naïve and memory T cells have not been evaluated. In this study we have detailed the dynamics of genome-wide promoter H3K4me2 and H3K4me3 over a time course during activation of human naïve and memory CD4 T cells. Our results demonstrate that changes to H3K4 methylation predominantly occur relatively late after activation (120 hours) and reinforce activation-induced upregulation of gene expression affecting multiple pathways important to T cell activation, differentiation, and function. The dynamics and mapped pathways of H3K4 methylation are distinctly different in memory cells. Memory CD4 have substantially more promoters marked by H3K4me3 alone, and that is influenced by promoter CpG content, reinforcing their more differentiated state. Our study provides the first data examining genome-wide histone modification dynamics during T cell activation, providing insight into the cross-talk between H3K4 methylation and gene expression, and underscoring the impact of these marks upon key pathways integral to CD4 T cell activation and function. ChIP-Seq for H3K4me2, H3K4me3, and H3K27me3 in naïve and memory CD4 T cells at rest and at 3 time points after activation with anti-CD3/CD28.
2016-06-01 | E-GEOD-73212 | biostudies-arrayexpress
Project description:The epigenetic determinants driving the rapid responses of memory CD4 T cells to antigen are currently an area of active research. While much has been done to characterize various Th subsets and their associated genome-wide epigenetic patterns, the dynamics of histone modifications during CD4 T cell activation and the differential kinetics of these epigenetic marks between naïve and memory T cells have not been evaluated. In this study we have detailed the dynamics of genome-wide promoter H3K4me2 and H3K4me3 over a time course during activation of human naïve and memory CD4 T cells. Our results demonstrate that changes to H3K4 methylation predominantly occur relatively late after activation (120 hours) and reinforce activation-induced upregulation of gene expression affecting multiple pathways important to T cell activation, differentiation, and function. The dynamics and mapped pathways of H3K4 methylation are distinctly different in memory cells. Memory CD4 have substantially more promoters marked by H3K4me3 alone, and that is influenced by promoter CpG content, reinforcing their more differentiated state. Our study provides the first data examining genome-wide histone modification dynamics during T cell activation, providing insight into the cross-talk between H3K4 methylation and gene expression, and underscoring the impact of these marks upon key pathways integral to CD4 T cell activation and function.
2016-06-01 | GSE73212 | GEO
Project description:The epigenetic determinants driving the rapid responses of memory CD4 T cells to antigen are currently an area of active research. While much has been done to characterize various Th subsets and their associated genome-wide epigenetic patterns, the dynamics of histone modifications during CD4 T cell activation and the differential kinetics of these epigenetic marks between naïve and memory T cells have not been evaluated. In this study we have detailed the dynamics of genome-wide promoter H3K4me2 and H3K4me3 over a time course during activation of human naïve and memory CD4 T cells. Our results demonstrate that changes to H3K4 methylation predominantly occur relatively late after activation (120 hours) and reinforce activation-induced upregulation of gene expression affecting multiple pathways important to T cell activation, differentiation, and function. The dynamics and mapped pathways of H3K4 methylation are distinctly different in memory cells. Memory CD4 have substantially more promoters marked by H3K4me3 alone, and that is influenced by promoter CpG content, reinforcing their more differentiated state. Our study provides the first data examining genome-wide histone modification dynamics during T cell activation, providing insight into the cross-talk between H3K4 methylation and gene expression, and underscoring the impact of these marks upon key pathways integral to CD4 T cell activation and function. RNA-Seq of naïve and memory CD4 T cells at rest and at 3 time points after activation with anti-CD3/CD28.
2016-06-01 | E-GEOD-73213 | biostudies-arrayexpress
Project description:The epigenetic determinants driving the rapid responses of memory CD4 T cells to antigen are currently an area of active research. While much has been done to characterize various Th subsets and their associated genome-wide epigenetic patterns, the dynamics of histone modifications during CD4 T cell activation and the differential kinetics of these epigenetic marks between naïve and memory T cells have not been evaluated. In this study we have detailed the dynamics of genome-wide promoter H3K4me2 and H3K4me3 over a time course during activation of human naïve and memory CD4 T cells. Our results demonstrate that changes to H3K4 methylation predominantly occur relatively late after activation (120 hours) and reinforce activation-induced upregulation of gene expression affecting multiple pathways important to T cell activation, differentiation, and function. The dynamics and mapped pathways of H3K4 methylation are distinctly different in memory cells. Memory CD4 have substantially more promoters marked by H3K4me3 alone, and that is influenced by promoter CpG content, reinforcing their more differentiated state. Our study provides the first data examining genome-wide histone modification dynamics during T cell activation, providing insight into the cross-talk between H3K4 methylation and gene expression, and underscoring the impact of these marks upon key pathways integral to CD4 T cell activation and function.
2016-06-01 | GSE73213 | GEO
Project description:Glioblastoma is a malignant brain tumor and one of the most lethal cancers in human. Temozolomide constitutes the standard chemotherapeutic agent, but only shows limited efficacy in glioblastoma patients with unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter status. Recently, it has been shown that glioblastoma cells communicate via particular ion-channels-so-called gap junctions. Interestingly, inhibition of these ion channels has been reported to render MGMT promoter-methylated glioblastoma cells more susceptible for a therapy with temozolomide. However, given the percentage of about 65% of glioblastoma patients with an unmethylated MGMT promoter methylation status, this treatment strategy is limited to only a minority of glioblastoma patients. In the present study we show that-in contrast to temozolomide-pharmacological inhibition of intercellular cytosolic traffic via gap junctions reinforces the antitumoral effects of chemotherapeutic agent lomustine, independent of MGMT promoter methylation status. In view of the growing interest of lomustine in glioblastoma first and second line therapy, these findings might provide a clinically-feasible way to profoundly augment chemotherapeutic effects for all glioblastoma patients.
| S-EPMC7997332 | biostudies-literature
Project description:Therapy-related and more specifically radiotherapy-associated acute myeloid leukaemia (AML) is a well-recognized potential complication of cytotoxic therapy for the treatment of a primary cancer. The CBA mouse model is used to study radiation leukaemogenesis mechanisms with Sfpi1/PU.1 deletion and point mutation already identified as driving events during AML development. To identify new pathways, we analysed 123 mouse radiation-induced AML (rAML) samples for the presence of mutations identified previously in human AML and found three genes to be mutated; Sfpi1 R235 (68%), Flt3-ITD (4%) and Kras G12 (3%), of which G12R was previously unreported. Importantly, a significant decrease in Sfpi1 gene expression is found almost exclusively in rAML samples without an Sfpi1 R235 mutation and is specifically associated with up-regulation of mir-1983 and mir-582-5p. Moreover, this down-regulation of Sfpi1 mRNA is negatively correlated with DNA methylation levels at specific CpG sites upstream of the Sfpi1 transcriptional start site. The down regulation of Sfpi1/PU.1 has also been reported in human AML cases revealing one common pathway of myeloid disruption between mouse and human AML where dysregulation of Sfpi1/PU.1 is a necessary step in AML development.
| S-EPMC7422620 | biostudies-literature
Project description:Recent transcription of GAL genes transiently leaves an H3K4 methylation mark at their promoters, providing an epigenetic memory for the recent transcriptional activity. However, the physiological significance of this mark is enigmatic. In our study, we show that the transient H3K4 di- and trimethylation at recently transcribed GAL1 inhibited the reinduction of GAL1. The H3K4 methylation functioned by recruiting the Isw1 ATPase onto GAL1 and thereby limiting the action of RNA polymerase II during GAL1 reactivation. Strikingly, the H3K4 methylation was also observed at the promoters of inositol- and fatty acid-responsive genes after recent transcription and played a negative role in their reinduction. Taken together, our data present a new mechanism by which H3K4 methylation regulates gene transcription.
| S-EPMC3186427 | biostudies-literature
Project description:The retrovirus restriction factor SAMHD1 is the first identified mammalian dNTP triphosphohydrolase that is highly expressed in human myeloid lineage cells and CD4(+) T lymphocytes. Although SAMHD1 expression is variable in human cell lines and tissue types, mechanisms underlying SAMHD1 gene regulation have not been defined. Recent studies showed that SAMHD1 is highly expressed in human primary CD4(+) T lymphocytes, but not in some CD4(+) T cell lines. Here, we report that SAMHD1 expression varies among four CD4(+) T cell lines and is transcriptionally regulated. Cloning and sequence analysis of the human SAMHD1 promoter revealed a CpG island that is methylated in CD4(+) T cell lines (such as Jurkat and Sup-T1), resulting in transcriptional repression of SAMHD1. We also found that the SAMHD1 promoter is unmethylated in primary CD4(+) T lymphocytes, which express high levels of SAMHD1, indicating a direct correlation between the methylation of the SAMHD1 promoter and transcriptional repression. SAMHD1 expression was induced in CD4(+) T cell lines by blocking DNA methyltransferase activity, suggesting that promoter methylation is one of the key epigenetic mechanisms by which SAMHD1 expression is regulated.
| S-EPMC3610999 | biostudies-literature