Recent insights into the transcriptional control of the<i>Tcra/Tcrd</i>locus by distant enhancers during the development of T-lymphocytes

Hernández-Munaín, Cristina

doi:10.1080/21541264.2015.1078429

Cited by 10 publications

(20 citation statements)

References 79 publications

(127 reference statements)

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“…The HS4-HS6 fragment contains the greatest enhancer blocking activity [39], with HS4 and HS6 being the major contributors that confer Eα-dependent high-level, position-independent and copy respectively; across the developmental stages by regulating the germline transcription and chromatin structure that mediates the accessibility of the recombinase machinery to each specific gene [46]. To permit the generation of functional Tcrd VDJ recombination and expression of the TCRδ chain in DN2/3a, Eδ is active whereas Eα remains inactive in these cells [14,46].…”

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

confidence: 99%

“…This strategy of successive Tcra VJ gene segment rearrangements using the further 5´-Trav/Trdv and 3´-Traj gene segments permits multiple VJ gene segment rearrangements at each Tcra allele to assure the expression of a productive TCRα chain in all lDP thymocytes and to provide a greater probability that positive selection and further αβ T lymphocyte maturation can occur. Eδ is formed by seven protein-bound elements known as δE1, δE2, δE3, δE4, δE5, δE6, and δE7, in a 380-bp DNA fragment [46]. Although this fragment is functional in activating transcription of reporter constructs in transient transfection experiments, it is not able to activate rearrangement of a reporter construct in single-copy transgenic mice requiring the presence of two flanking matrix attachment regions for such function [52].…”

mentioning

confidence: 99%

“…Interestingly, Eδ is inactivated during β-selection but presumably not during γδ-selection [14,43]. Therefore, both Eδ and Eα are relevant enhancers to dictate the patterns of the Tcrd and Tcra gene germline transcription and V(D)J recombination during thymocyte development [14,34,43,46].The Tcra VJ rearrangements are accomplished through activation of germline transcription, which is initiated at Eα-dependent promoters associated with the most 3´-Trav/Trdv and 5´-Traj gene segments and opens up the chromatin structure to provide accessibility for the recombination machinery in eDP thymocytes (Figure 2) [48][49][50]. These initial Tcra VJ gene segment rearrangements occur in eDP thymocytes and are known as primary Tcra VJ recombination (Figure 2) [50].…”

mentioning

confidence: 99%

“…Eδ activity depends critically on the binding of the transcription factors (TFs) Runx1 and c-Myb to δE3 [53][54][55]. These TFs are dissociated from Eδ in the transition from DN3a to DP thymocytes, which is concomitant with the inactivation of the enhancer [14].Eα is formed by four protein-bound elements known as Tα1, Tα2, Tα3, and Tα4, in a 275-bp DNA fragment that constitutes the minimal Eα with the correct temporal regulation during thymocyte development [46]. 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].…”

mentioning

confidence: 99%

“…The 3´-6-kb LCR fragment contains . HS2-6 is transcriptionally active in non T-lineage cells and collaborates with Eα to confer a high-level, position-independent and copy number-dependent transgene expression in T-lineage cells by acting as an insulator that blocks Eα activity to maintain the distinct regulatory programs of the neighboring Tcra/Tcrd and Dad1 genes [29,30,39].The HS4-HS6 fragment contains the greatest enhancer blocking activity [39], with HS4 and HS6 being the major contributors that confer Eα-dependent high-level, position-independent and copy respectively; across the developmental stages by regulating the germline transcription and chromatin structure that mediates the accessibility of the recombinase machinery to each specific gene [46]. To permit the generation of functional Tcrd VDJ recombination and expression of the TCRδ chain in DN2/3a, Eδ is active whereas Eα remains inactive in these cells [14,46].…”

mentioning

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

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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Direct regulation of TCR rearrangement and expression by E proteins during early T cell development

Anderson

Rocha

2022

WIREs Mechanisms of Disease

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γδ T cells are widely distributed throughout mucosal and epithelial cell‐rich tissues and are an important early source of IL‐17 in response to several pathogens. Like αβ T cells, γδ T cells undergo a stepwise process of development in the thymus that requires recombination of genome‐encoded segments to assemble mature T cell receptor (TCR) genes. This process is tightly controlled on multiple levels to enable TCR segment assembly while preventing the genomic instability inherent in the double‐stranded DNA breaks that occur during this process. Each TCR locus has unique aspects in its structure and requirements, with different types of regulation before and after the αβ/γδ T cell fate choice. It has been known that Runx and Myb are critical transcriptional regulators of TCRγ and TCRδ expression, but the roles of E proteins in TCRγ and TCRδ regulation have been less well explored. Multiple lines of evidence show that E proteins are involved in TCR expression at many different levels, including the regulation of Rag recombinase gene expression and protein stability, induction of germline V segment expression, chromatin remodeling, and restriction of the fetal and adult γδTCR repertoires. Importantly, E proteins interact directly with the cis‐regulatory elements of the TCRγ and TCRδ loci, controlling the predisposition of a cell to become an αβ T cell or a γδ T cell, even before the lineage‐dictating TCR signaling events. This article is categorized under: Immune System Diseases > Stem Cells and Development Immune System Diseases > Genetics/Genomics/Epigenetics

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A BCWD-resistant line of rainbow trout exhibits higher abundance of IgT+ B cells and heavy chain tau transcripts compared to a susceptible line following challenge with Flavobacterium psychrophilum

Zwollo

Hennessey

Moore

et al. 2017

Developmental & Comparative Immunology

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Bacterial Cold Water Disease (BCWD) is a common, chronic disease in rainbow trout, and is caused by the gram-negative bacterium Flavobacterium psychrophilum (Fp). Through selective breeding, the National Center for Cool and Cold Water Aquaculture has generated a genetic line that is highly resistant to Fp challenge, designated ARS-Fp-R (or R-line), as well as a susceptible “control” line, ARS-Fp-S (S-line). In previous studies, resistance to Fp had been shown to correlate with naive animal spleen size, and further, naïve R-line trout had been shown to have a lower abundance of IgM+ and IgM++ cells compared to S-line fish. Here we wished to first determine whether the abundance of IgT+ and/or IgT++ cells differed between the two lines in naïve fish, and if so, how these patterns differed after in vivo challenge with Fp. Fp challenge was by intramuscular injection of live Fp and tissue collections were on days 5, 6, and/or 28 post-challenge, in two independent challenge experiments. Flow cytometric and gene expression analyses revealed that naïve R-line fish had a higher abundance of IgT+ B cells in their anterior kidney, spleen, and blood, compared to S line fish. Further, that after Fp challenge, this difference was maintained between the two lines. Lastly, abundance of IgT+ B cells and expression of secHCtau correlated with lower Fp pathogen loads in challenged fish. In the anterior kidney, IgM+ B cell abundance correlated with increased Fp loads. Together, these results suggest that IgT+ B lineage cells may have a protective function in the immune response to Fp.

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

Cited by 10 publications

References 79 publications

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

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

Direct regulation of TCR rearrangement and expression by E proteins during early T cell development

A BCWD-resistant line of rainbow trout exhibits higher abundance of IgT+ B cells and heavy chain tau transcripts compared to a susceptible line following challenge with Flavobacterium psychrophilum

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