Schlafen, a New Family of Growth Regulatory Genes that Affect Thymocyte Development

Schwarz, David; Katayama, Carol D.; Hedrick, Stephen M.

doi:10.1016/s1074-7613(00)80663-9

Cited by 199 publications

(279 citation statements)

References 45 publications

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“…Several genes involved in cellular differentiation rather than activation, such as ornithine decarboxylase, B cell translocation gene 1 (BTG 1), JunB, and Schlafen 2, show ''high-moderate'' expression in SP thymocytes. Expression of BTG 1 and BTG 2 and Schlafen 2 is up-regulated in quiescent lymphocytes and may maintain cells in G 0 ͞G 1 (26,27). JunB, which can also maintain highly differentiated cells in the resting state (16), is expressed at higher levels in CD4 vs. CD8 SP thymocytes (21 vs. 4) (Fig.…”

Section: Resultsmentioning

confidence: 96%

Detailed analysis of gene expression during development of T cell lineages in the thymus

McCarty

Shinohara

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The genetic mechanisms that promote lineage commitment and eliminate autoreactive cells in the thymus are not well understood. To better understand this process, we have identified and quantitated transcripts in the two major thymocyte lineages by using serial analysis of gene expression. Approximately 25 genes displayed almost complete segregation to one or the other T cell lineage. Commitment to the CD4 lineage was marked by upregulation of genes associated with increased survival and chaperone function followed by expression of genes that regulate nucleosome remodeling and T cell receptor signaling. Differentiation within the CD8 lineage, on the other hand, was marked by up-regulation of genes that regulate lymphocyte homing, followed by quenching of genes that inhibit apoptosis. Definition of differential gene expression during development of the two major thymocyte lineages will allow insight into mechanisms of T cell development after positive and negative selection.serial analysis of gene expression ͉ genetic profiling ͉ CD4͞CD8 ͉ lineage commitment T he two major T cell lineages that regulate adaptive immunity are generated and purged of clones bearing autoreactive T cell receptors (TCR) in the thymus (1). Although the molecular basis of TCR expression on thymocytes and T cells is relatively well understood, the mechanisms that orchestrate development and selection of TCR-bearing thymocytes have not been clearly defined. Delineation of the expression and potential function of genes expressed during the development of each lineage represents an important step in understanding this process.Thymocyte differentiation begins with migration of common lymphoid progenitor cells from hematopoietic stem cells in adult bone marrow or fetal liver into the thymus, where they undergo cellular maturation and TCR-based selection. Distinct developmental compartments have been defined according to expression of the CD4 and CD8 coreceptors on differentiating thymocytes. The earliest compartment is composed of CD4 Ϫ 8 Ϫ double negative (DN) thymocytes, which give rise to CD4 ϩ CD8 ϩ double positive (DP) intermediates, which yield mature CD4 ϩ CD8 Ϫ (CD4) or CD4 Ϫ CD8 ϩ (CD8) single positive (SP) mature progeny. The DN stage of thymocyte differentiation is marked by genetic events that prepare cells for TCR-based selection by self-MHC, including expression of recombination activating genes (RAG-1 and RAG-2) and initiation of TCR␤ gene rearrangements. These genetic events can be demarcated according to surface markers expressed sequentially on DN thymocytes (stages DN1-DN4) in order of their appearance during development (2, 3). DN1 and DN2 thymocytes proliferate before RAG-1͞-2 expression (4, 5), whereas the DN3 3 DN4 developmental step is accompanied by expression of a pre-TCR that inhibits further RAG-1͞-2 activity and promotes a second proliferative burst of cells that express both CD4 and CD8, marking transition into the DP compartment (6).Thymocytes that express the DP phenotype (by far the most abundant in the thymus) ...

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Section: Resultsmentioning

confidence: 96%

Detailed analysis of gene expression during development of T cell lineages in the thymus

McCarty

Shinohara

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…One large category representing 44 of the 177 differentially expressed genes are genes induced during positive selection but not by TCR signaling. This category includes many genes previously described to be induced during positive selection, such as CD53, IL-6R␣, and schlafen 1 (18)(19)(20), and some genes whose expression pattern during positive selection has not been previously characterized, such as semaphorin 4A, PKC-, and the serine protease inhibitor, serpin1b. This cluster may include genes that require thymic stromal cell factors in addition to TCR signaling for their induction.…”

Section: Resultsmentioning

confidence: 99%

Distinct transcriptional programs in thymocytes responding to T cell receptor, Notch, and positive selection signals

Huang

Winoto

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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T cell antigen receptor (TCR) signaling is necessary but not sufficient to promote the positive selection of CD4 ؉ CD8 ؉ thymocytes into CD4 ؉ or CD8 ؉ mature T cells. Notch signaling has also been implicated as a potential regulator of both CD4͞CD8 T cell development and TCR signaling. However, the relationship between positive selection, TCR signaling, and Notch remains unclear. Here we use DNA microarray analysis to compare gene expression changes in CD4 ؉ CD8 ؉ double-positive thymocytes undergoing positive selection, TCR stimulation, and Notch activation. We find that the genes induced during positive selection can be resolved into two distinct sets. One set, which we term ''TCR-induced,'' is also induced by in vitro TCR stimulation and contains a large proportion of transcription factors. A second set, which we term ''positive-selection-induced,'' is not induced by in vitro TCR simulation and contains a large proportion of genes involved in signal transduction pathways. Genes induced by Notch activity overlap substantially with genes induced during positive selection. We also find that Notch activity potentiates the effects of TCR stimulation on gene expression. These results help to identify TCR-and positive-selection-specific transcriptional events and help to clarify the relationship between positive selection and Notch.microarray ͉ gene expression profile ͉ negative selection

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“…42,43 SLFN11, a member of the SLFN family, potently and specifically abrogates the production of retroviruses, e.g., human immunodeficiency virus (HIV-1). 33 Using cells with endogenously high and low SLFN11 expression and siRNA-mediated silencing, Zoppoli et al 44 found that SLFN11 causally determines cell death and cell cycle arrest in response to DNA-damaging agents in cancer cells from different tissues of origin.…”

Section: Discussionmentioning

confidence: 99%

Differential DNA methylation and PM_2.5 species in a 450K epigenome-wide association study

et al. 2017

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Although there is growing evidence that exposure to ambient particulate matter is associated with global DNA methylation and gene-specific methylation, little is known regarding epigenome-wide changes in DNA methylation in relation to particles and, especially, particle components. Using the Illumina Infinium HumanMethylation450 BeadChip, we examined the relationship between one-year moving averages of PM 2.5 species (Al, Ca, Cu, Fe, K, Na, Ni, S, Si, V, and Zn) and DNA methylation at 484,613 CpG probes in a longitudinal cohort that included 646 subjects. Bonferroni correction was applied to adjust for multiple comparisons. Bioinformatics analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was also performed. We observed 20 Bonferroni significant (P-value < 9.4£ 10 ¡9 ) CpGs for Fe, 8 for Ni, and 1 for V. Particularly, methylation at Schlafen Family Member 11 (SLFN11) cg10911913 was positively associated with measured levels of all 3 species. The SLFN11 gene codes for an interferoninduced protein that inhibits retroviruses and sensitizes cancer cells to DNA-damaging agents. Bioinformatics analysis suggests that gene targets may be relevant to pathways including cancers, signal transduction, and cell growth and death. Ours is the first study to examine the epigenome-wide association between ambient particles species and DNA methylation. We found that long-term exposures to specific components of ambient particle pollution, especially particles emitted during oil combustion, were associated with methylation changes in genes relevant to immune responses. Our findings provide insight into potential biologic mechanisms on an epigenetic level.

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Schlafen, a New Family of Growth Regulatory Genes that Affect Thymocyte Development

Cited by 199 publications

References 45 publications

Detailed analysis of gene expression during development of T cell lineages in the thymus

Detailed analysis of gene expression during development of T cell lineages in the thymus

Distinct transcriptional programs in thymocytes responding to T cell receptor, Notch, and positive selection signals

Differential DNA methylation and PM_2.5 species in a 450K epigenome-wide association study

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Schlafen, a New Family of Growth Regulatory Genes that Affect Thymocyte Development

Cited by 199 publications

References 45 publications

Detailed analysis of gene expression during development of T cell lineages in the thymus

Detailed analysis of gene expression during development of T cell lineages in the thymus

Distinct transcriptional programs in thymocytes responding to T cell receptor, Notch, and positive selection signals

Differential DNA methylation and PM2.5 species in a 450K epigenome-wide association study

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Differential DNA methylation and PM_2.5 species in a 450K epigenome-wide association study