Unknown,Transcriptomics,Genomics,Proteomics

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Promoter H3K4 methylation reveals the dynamic reinforcement of activation-induced pathways in human CD4 T cells with differential kinetics in naÃ¯ve and memory cells (RNA-Seq)

ABSTRACT: 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 naÃ¯ve 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 naÃ¯ve 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 naÃ¯ve and memory CD4 T cells at rest and at 3 time points after activation with anti-CD3/CD28.

ORGANISM(S): Homo sapiens

SUBMITTER: Ryan Thompson

PROVIDER: E-GEOD-73213 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Innate memory phenotype (IMP) CD4+ T cells are non-conventional Î±Î² T cells exhibiting features of innate immune cells, characterized as CD44high and CD62Llow in periphery. It is recently reported by our group that bone marrow chimeric mice lacking thymic MHCI expression develop predominantly IMP CD8+ T cells, while those lacking hematopoietic MHCI develop predominantly naÃ¯ve CD8+ T cells. Here we perform hirarchical clustering analysis and found that CD4+ T cells share similar property: chimeras lacking thymic MHCII gave rise to predominantly CD4+ T cells that resemble IMP CD4+ T cells observed in WT mice, and vice versa, chimeras lacking hematopoietic MHCII had a majority of naÃ¯ve-like CD4+ T cells resembling naÃ¯veCD4+ T cells seen in WT mice. We used microarrays to compare the global programme of gene expression to determine whether the hematopoietic MHCII selected CD4+ T cells are IMP, and whether the thymic MHCII selected CD4+ T cells are naÃ¯ve CD4+ T cells as observed in WT mice. Through hierarchical clustering and analysis of global gene differential expression, we determined that hematopoietic MHCII dependent IMP CD4+ T cells generated from WT bone marrow transplanted into irradiated MHCII-/- recipients, resemble IMP CD4+ T cells in WT mice, while naÃ¯ve CD4+ T cells generated from MHCII-/- bone marrow transplanted into irradiated WT recipients, resemble naÃ¯ve CD4+ T cells in WT mice. Cell Sorting was performed using a Cytopeia Influx Cell Sorter. Chimeric IMP (CD45.1+TCRÎ²+CD4+CD44highCD62Llow) CD4+ T cells were sorted from splenocytes of CD45.1+WTâCD45.2+MHCII-/- chimeras (WM IMP CD4), and chimeric naÃ¯ve (CD45.2+TCRÎ²+CD4+CD44lowCD62Lhigh) CD4+ T cells were sorted from splenocytes of CD45.2+MHCII-/- â CD45.1+WT chimeras (MW naÃ¯ve CD4) respectively, 8 weeks post transplantation. WT IMP (TCRÎ²+CD4+CD44highCD62Llow) and naÃ¯ve (TCRÎ²+CD4+CD44lowCD62Lhigh) CD4+ T cells were sorted from splenocytes of 8-week old WT mice.

Project description:Memory B cells play essential roles in the maintenance of long-term immunity and may be important in the pathogenesis of autoimmune disease, but how these cells are distinguished from their naÃ¯ve precursors is poorly understood. To address this, it would be important to understand how gene expression differs between memory and naive B cells in order to elucidate memory-specific functions. Using model systems that help overcome the lack of murine memory-specific markers and the low frequency of antigen-specific memory and naÃ¯ve cells, we undertook a global comparison of gene expression between memory B cells and their naive precursors. 1st generation screen:; These data represent our first generation comparison of gene expression between murine naÃ¯ve and memory splenic B cells. NaÃ¯ve NP-binding splenic B cells were FACS purified from unimmunized mVh186.2 transgenic Balb/c mice. Memory B cells were generated by immunizing mVh186.2 transgenic Balb/c mice with 2 doses of NP-CGG in alum delivered i.p. 6 weeks apart. After a minimum of 12-weeks rest, NP-binding splenic B cells were isolated by FACS. Total RNA was extracted, cRNA synthesized and labeled and hybridized to Affymetrix mouse 430 2.0 chips. 2nd generation screen:; These data represent our second generation comparison of gene expression between murine naÃ¯ve and memory splenic B cells. NaÃ¯ve NP-binding AA4.1neg splenic B cells were FACS purified from unimmunized mVh186.2 transgenic Jk KO Balb/c mice. Memory B cells were generated from these naive precursors after adoptive transfer into recipients that mount poor endogenous NP-responses. 12-weeks post i.p. immunization with NP-CGG in alum, NP-specific splenic memory B cells were isolated by FACS. Total RNA was extracted, cRNA synthesized and labeled and hybridized to Affymetrix mouse 430 2.0 chips. Memory/NaÃ¯ve comparison data linked below as Supplementary files. SERIES_CITATION: Tomayko, MM, Anderson, SM, Brayton CE, Sadanand, S, Steinel NC, Behrens, TW, Shlomchik, MJ. 2008. Systematic comparison of gene expression between murine memory and naÃ¯ve B cells demonstrates that memory B cells have unique signaling capabilities. J. Immunol., in press, 2008. Experiment Overall Design: 1st generation screen: 7 samples, 3-4 biological replicates each of murine splenic naÃ¯ve and memory B cells Experiment Overall Design: 2nd generation screen: 8 samples, 4 biological replicates each of murine splenic naÃ¯ve and memory B cells

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Promoter H3K4 methylation reveals the dynamic reinforcement of activation-induced pathways in human CD4 T cells with differential kinetics in naÃ¯ve and memory cells (RNA-Seq)

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