TCRalpha enhancer activation occurs via a conformational change of a pre-assembled nucleo-protein complex

Spicuglia, Salvatore; Payet, Dominique; Tripathi, Raj Kamal; Rameil, Pascal; Verthuy, Christophe; Imbert, Jean; Ferrier, Pierre; Hempel, William M.

doi:10.1093/emboj/19.9.2034

Cited by 36 publications

(48 citation statements)

References 57 publications

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“…Specifically, we probed Vβ cross-linking to HindIII fragments containing either of its two substrates (Dβ1 or Dβ2), or the transcriptional enhancer Eβ, which generates active chromatin over the DβJβ clusters (10,31). Regardless of the vantage point, nearly all Vβ gene segments interact more frequently with the DβJβ recombination center in DN thymocytes compared with CD19 + pro-B cells purified from RAG-deficient bone marrow ( Fig.…”

Section: Spatial Access Of Vβ Gene Segments To the Dβjβ Recombinationmentioning

confidence: 99%

Unifying model for molecular determinants of the preselection Vβ repertoire

Gopalakrishnan

Majumder

Predeus

et al. 2013

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

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The primary antigen receptor repertoire is sculpted by the process of V(D)J recombination, which must strike a balance between diversification and favoring gene segments with specialized functions. The precise determinants of how often gene segments are chosen to complete variable region coding exons remain elusive. We quantified Vβ use in the preselection Tcrb repertoire and report relative contributions of 13 distinct features that may shape their recombination efficiencies, including transcription, chromatin environment, spatial proximity to their DβJβ targets, and predicted quality of recombination signal sequences (RSSs). We show that, in contrast to functional Vβ gene segments, all pseudo-Vβ segments are sequestered in transcriptionally silent chromatin, which effectively suppresses wasteful recombination. Importantly, computational analyses provide a unifying model, revealing a minimum set of five parameters that are predictive of Vβ use, dominated by chromatin modifications associated with transcription, but largely independent of precise spatial proximity to DβJβ clusters. This learned model-building strategy may be useful in predicting the relative contributions of epigenetic, spatial, and RSS features in shaping preselection V repertoires at other antigen receptor loci. Ultimately, such models may also predict how designed or naturally occurring alterations of these loci perturb the preselection use of variable gene segments.lymphocytes | T-cell receptor | gene regulation G ene activity is regulated at multiple levels to coordinate expression during development. At a most basic level, the collection of cis-acting elements for a genetic locus recruits transcription factors that alter its chromatin environment to either induce or repress gene activity. Emerging studies indicate that the 3D conformation of a locus also plays an important role in the regulation of its composite genes (1). At most genes, many levels of control are integrated to achieve the requisite gene expression state. For example, transcriptional promoters interact with their cognate enhancers over considerable distances in the linear genome to generate "hubs" where the two cis elements are in spatial proximity (1, 2).All of these regulatory strategies are used to generate functional Ig (Ig) and T-cell receptor (Tcr) genes during lymphocyte development (3). Each antigen receptor (AgR) locus is composed of multiple variable (V), joining (J), and sometimes diversity (D) gene segments that are assembled by the process of V (D)J recombination, creating a potential variable region exon (4). Recombination is mediated by the RAG-1/2 enzymatic complex, which is expressed in all developing lymphocytes and recognizes semiconserved recombination signal sequences (RSSs) flanking all AgR gene segments (5). On selection of two compatible gene segments by RAG-1/2, recombination proceeds via a DNA break/repair mechanism, ultimately fusing the two selected segments (4, 5).The assembly of AgR genes is strictly regulated despite a common collection of ge...

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Section: Spatial Access Of Vβ Gene Segments To the Dβjβ Recombinationmentioning

confidence: 99%

Unifying model for molecular determinants of the preselection Vβ repertoire

Gopalakrishnan

Majumder

Predeus

et al. 2013

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

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“…The 116-bp Tα1-Tα2 fragment constitutes the core enhancer with essential binding sites for the constitutive TFs CREB/ ATF, TCF-1/LEF-1, Runx1, and Ets-1 that bind cooperatively in an allor-none fashion [36,[56][57][58]. These TFs are bound to a primed Eα prior to its activation in DN3a thymocytes as well as when the enhancer is fully active in eDP and lDP thymocytes [14,46,59]. Although the Tα1-Tα2 fragment is efficient in activating transcription and gene segment recombination at short distances in the context of a transgenic recombination reporter construct, is not sufficient to activate endogenous Tcra VJ recombination at large distances [36,60].…”

Section: Regulatory Cis-elements Present At the Tcra/tcrd Locusmentioning

confidence: 99%

“…Recent experiments using chromatin immunoprecipitation to compare the active and inactive Eα enhanceosomes assembled in DP thymocytes and αβ T lymphocytes, respectively, have revealed that the [14,[57][58][59]62,76]. The TFs are represented by colored ovals and their identity is indicated.…”

Section: Eα and Eδ In Mature αβ And γδ T Lymphocytesmentioning

confidence: 99%

“…In support of this hypothesis, transgenic rearranged Tcra constructs containing the 3-kb region from the downstream Cα, including Eα and HS1´, are expressed at very low and variable levels, ranging from 1 to 20% in αβ T lymphocytes [29,64]. Two main questions rise from these findings: How is Eα inactivated and what is the molecular mechanism for transcribing the rearranged Tcra locus in SP thymocytes and αβ T cells?Recent experiments using chromatin immunoprecipitation to compare the active and inactive Eα enhanceosomes assembled in DP thymocytes and αβ T lymphocytes, respectively, have revealed that the [14,[57][58][59]62,76]. The TFs are represented by colored ovals and their identity is indicated.…”

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confidence: 99%

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Insights into the Transcriptional Regulation of the Unrearranged and Rearranged Tcra and Tcrd Genes

Hernández-Munaín¹,

Casal²,

Juanes³

et al. 2016

J Clin Cell Immunol

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The combined T-cell receptor α and δ locus, Tcra/Tcrd, encodes the TCRα and TCRδ chains of the αβ or γδ T-cell receptors (TCRαβ and TCRγδ), respectively, which define the two distinct T-cell lineages, αβ and γδ T lymphocytes. Like other antigen receptor loci, this locus must recombine its variable (V), diversity (D), and joining (J) gene segments to generate a diverse range of TCR that allow vertebrates to respond to an unlimited number of antigens. The Tcra/Tcrd germline transcription and subsequent V(D)J gene segment rearrangements are strictly regulated by two distant transcriptional enhancers, Eα and Eδ, respectively, during thymocyte development. Once the Tcra locus is productively rearranged, it is assumed Eα remains active for the transcription of the rearranged locus and the expression of the functional TCRα chain in αβ T lymphocytes. However, our recent experiments have shown Eα is significantly inhibited during the final stage of thymocyte development, concomitantly with the expression of the rearranged Tcra locus, and remains inhibited in αβ T lymphocytes. These results imply the existence of an Eα-independent mechanism to activate transcription of the rearranged Tcra locus in αβ T lymphocytes. Interestingly, Eα is essential for the normal expression of the rearranged Tcrd locus in γδ T lymphocytes. In this review, the current knowledge about the regulation of Tcra/Tcrd germline transcription and gene segment rearrangement during thymocyte development and the possible mechanisms for transcription of the rearranged Tcra locus in mature αβ T lymphocytes are discussed. The knowledge of the detailed mechanisms involved in the regulation of transcription at the Tcra/Tcrd locus by distant enhancers is important to understand the cases in which deregulation this process results in disease. Keywords: Transcription; T-cell receptor; V(D)J recombination; Enhancer Abbreviations:A Temporal Control of TCR Gene RearrangementsDuring thymic T-cell development (Figure 1), early T-cell progenitors (ETP) arising from fetal liver or bone marrow enter to the thymus, where they mature progressively through different stages that can be distinguished based on the expression of the CD4 and CD8 surface markers: CD4-CD8-double-negative (DN) thymocytes, immature single-positive (ISP) CD8 + thymocytes, CD4 + CD8 + doublepositive (DP) thymocytes, and CD4 + or CD8 + single-positive (SP) thymocytes [1]. Among the DN thymocyte population, four subpopulations can be further distinguished based on the expression of CD25 and CD44 surface markers: DN1 (CD44 + CD25 -), DN2 (CD44 + CD25 + ), DN3 (CD44 -CD25 + ), and DN4 (CD44 -CD25 -) thymocytes. In addition, two DN3 subpopulations can be distinguished based on the expression of CD27: DN3a (CD27 low ) and DN3b (CD27 high ) thymocytes [2]. Furthermore, two DP thymocyte populations can be distinguished based on the expression of CD71: early DP (eDP) (CD71 + ) and late DP (lDP) (CD71 -) thymocytes [3]. For αβ T-cell development, thymocytes transition from DN1 to SP thymocytes by matu...

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“…23 During these early thymocyte stages, Ea is not functionally active but is primed through the assembly of multiple constitutive TFs that bind cooperatively to enhancer DNA and the presence of the H3K4me1 histone mark. [31][32][33][34][35] During b-selection, Ea is activated and Ed is inactivated during the transition from DN3a to DP thymocytes. 32 Pre-TCR signaling triggers the formation of a chromatin hub through physical interactions among TFs bound to the Ea enhanceosome and Ca-proximal Va-and Ca-distal Ja promoters in a genomic region of approximately 500 kb.…”

Section: 19mentioning

confidence: 99%

Recent insights into the transcriptional control of theTcra/Tcrdlocus by distant enhancers during the development of T-lymphocytes

Hernández-Munaín

2015

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TCRalpha enhancer activation occurs via a conformational change of a pre-assembled nucleo-protein complex

Cited by 36 publications

References 57 publications

Unifying model for molecular determinants of the preselection Vβ repertoire

Unifying model for molecular determinants of the preselection Vβ repertoire

Insights into the Transcriptional Regulation of the Unrearranged and Rearranged Tcra and Tcrd Genes

Recent insights into the transcriptional control of theTcra/Tcrdlocus by distant enhancers during the development of T-lymphocytes

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