Transcription-Dependent Generation of a Specialized Chromatin Structure at the TCRβ Locus

Zacarías-Cabeza, Joaquin; Belhocine, Mohamed; Vanhille, Laurent; Cauchy, Pierre; Koch, Frank‐Thomas; Pękowska, Aleksandra; Fenouil, Romain; Bergon, Aurélie; Gut, Marta; Eick, Dirk; Imbert, Jean; Ferrier, Pierre; Andrau, Jean-Christophe; Spicuglia, Salvatore

doi:10.4049/jimmunol.1400789

Cited by 14 publications

(23 citation statements)

References 52 publications

(98 reference statements)

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“…We have previously suggested that the Eα enhancer activation occurs via a conformational change of a preassembled nucleo-protein complex (Cauchy et al, 2016;Spicuglia et al, 2000). Analysis of published ChIP-seq experiments for ETS1, RUNX1, E47/TCF3, GATA3, and Ikaros lymphoid transcription factors (Zacarías-Cabeza et al, 2015;Koch et al, 2011;Lepoivre et al, 2013;Wei et al, 2011;Vanhille et al, 2015;Oravecz et al, 2015) confirmed that Eα is already occupied by these activating transcription factors in murine DN thymocytes ( Fig. S4 A).…”

Section: Dna Demethylation Is a Hallmark Of Distal Regulatory Elementsupporting

confidence: 54%

Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation

Cieślak¹,

Charbonnier

Tesio³

et al. 2020

Journal of Experimental Medicine

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Cell differentiation is accompanied by epigenetic changes leading to precise lineage definition and cell identity. Here we present a comprehensive resource of epigenomic data of human T cell precursors along with an integrative analysis of other hematopoietic populations. Although T cell commitment is accompanied by large scale epigenetic changes, we observed that the majority of distal regulatory elements are constitutively unmethylated throughout T cell differentiation, irrespective of their activation status. Among these, the TCRA gene enhancer (Eα) is in an open and unmethylated chromatin structure well before activation. Integrative analyses revealed that the HOXA5-9 transcription factors repress the Eα enhancer at early stages of T cell differentiation, while their decommission is required for TCRA locus activation and enforced αβ T lineage differentiation. Remarkably, the HOXA-mediated repression of Eα is paralleled by the ectopic expression of homeodomain-related oncogenes in T cell acute lymphoblastic leukemia. These results highlight an analogous enhancer repression mechanism at play in normal and cancer conditions, but imposing distinct developmental constraints.

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Section: Dna Demethylation Is a Hallmark Of Distal Regulatory Elementsupporting

confidence: 54%

Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation

Cieślak¹,

Charbonnier

Tesio³

et al. 2020

Journal of Experimental Medicine

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“…For successful V(D)J recombination to occur, the lymphoid‐specific RAG1/2 recombinases need to have access to the respective loci, and transcriptional enhancers and promoters control this process via the modulation of the chromatin structure . Moreover, it has been shown that high and extended H3K4me3 marks are present throughout the D β ‐J β ‐C β gene segments of the TCRB locus which depends on RNA polymerase II‐mediated transcriptional activity, which together with the extended H3K4 trimethylation renders D β and J β gene segments highly accessible . It is also important to note that specific TCRD gene rearrangements occur in a strict order which is dependent on RUNX proteins.…”

Section: γδ T Cells Versus αβ T Cells: What About Epigenetics?mentioning

confidence: 99%

Stochastics of Cellular Differentiation Explained by Epigenetics: The Case of T‐Cell Differentiation and Functional Plasticity

et al. 2017

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Epigenetic marks including histone modifications and DNA methylation are associated with the regulation of gene expression and activity. In addition, an increasing number of non-coding RNAs with regulatory activity on gene expression have been identified. Alongside, technological advancements allow for the analysis of these mechanisms with high resolution up to the single-cell level. For instance, the assay for transposase-accessible chromatin using sequencing (ATAC-seq) simultaneously probes for chromatin accessibility and nucleosome positioning. Thus, it provides information on two levels of epigenetic regulation. Development and differentiation of T cells into functional subset cells including memory T cells are dynamic processes driven by environmental signals. Here, we briefly review the current knowledge of how epigenetic regulation contributes to subset specification, differentiation and memory development in T cells. Specifically, we focus on epigenetic mechanisms differentially active in the two distinct T cell populations expressing ab or cd T cell receptors. We also discuss examples of epigenetic alterations of T cells in autoimmune diseases. DNA methylation and histone acetylation are subject to modification by several classes of 'epigenetic modifiers', some of which are in clinical use or in preclinical development. Therefore, we address the impact of some epigenetic modifiers on T-cell activation and differentiation, and discuss possible synergies with T cellbased immunotherapeutic strategies.

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“…In DN thymocytes, TCR gene activation for recombination depends on cooperative outputs from cis-regulatory elements, including the transcriptional enhancer E and D -flanking promoters pD s (Sikes and Oltz, 2012). At this stage, attributes of relaxed chromatin (Pol-II-generated GL transcripts, CpG demethylation, active histone marks, positioned arrays of nucleosomes) are evident in the genomic regions that encompass the D and J gene segments (Morshead et al, 2003;Kondilis-Mangum et al, 2010;Zacarias-Cabeza et al, 2015). These permit the local recruitment of RAG machinery to form a so-called recombination center (Ji et al, 2010b), and also may optimize lineagespecific release of TCR alleles from suppressive peripheral subnuclear positioning (Schlimgen et al, 2008;Chan et al, 2013).…”

Section: Modeling the Dynamics Of Tcr Recombination In Single Developmentioning

confidence: 99%

A dynamical model of TCRβgene recombination: Coupling the initiation of Dβ-Jβrearrangement to TCRβallelic exclusion

Jaeger

Lima

Meyroneinc

et al. 2017

Preprint

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One paradigm of random monoallelic gene expression is that of T-cell receptor (TCR) allelic exclusion in T lymphocytes. However, the dynamics that sustain asymmetric choice in TCR dual allele usage and the production of TCR monoallelic expressing T-cells remain poorly understood. Here, we develop a computational model to explore a scheme of TCR allelic exclusion based on the stochastic initiation of DNA rearrangement [V(D)J recombination] at homologous alleles in T-cell progenitors, and thus account for the genotypic profiles typically associated with allelic exclusion in differentiated T-cells. Disturbances in these dynamics at the level of an individual allele have limited consequences on these profiles, a robust feature of the system that is underscored by our simulations. Our study predicts a biological system in which locus-specific, prime epigenetic allelic activation effects set the stage to both optimize the production of TCR allelically excluded T-cells and curtail the emergence of their allelically included counterparts.

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Transcription-Dependent Generation of a Specialized Chromatin Structure at the TCRβ Locus

Abstract: International audienceno abstrac

Cited by 14 publications

References 52 publications

Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation

Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation

Stochastics of Cellular Differentiation Explained by Epigenetics: The Case of T‐Cell Differentiation and Functional Plasticity

A dynamical model of TCRβgene recombination: Coupling the initiation of Dβ-Jβrearrangement to TCRβallelic exclusion

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