TEA regulates local TCR‐Jα accessibility through histone acetylation

Mauvieux, Laurent; Villey, Isabelle; Villartay, Jean‐Pierre de

doi:10.1002/eji.200323867

Cited by 16 publications

(11 citation statements)

References 27 publications

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“…Another example is the motif recognized by the four TEAD family members, which is associated with enhancer marks H3K27ac (all cell-types) and H3K4me1 (TBL only). Remarkably, our finding is consistent with a previous study showing that deletion of a TEAD binding site from upstream of TCRJα locus resulted in a loss of H3 histone acetylation 44 . Furthermore, TEAD family members are known to promote cell proliferation by interacting with the Hippo signaling pathway 45 , which is critical for self-renewal and expansion of ESC into lineage-specific progenitors 46 .…”

Section: Resultssupporting

confidence: 93%

Predicting the human epigenome from DNA motifs

2014

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The epigenome is established and maintained by the site-specific recruitment of chromatin-modifying enzymes and their co-factors. Identifying the cis-elements that regulate epigenomic modification is critical to understand the regulatory mechanisms that control gene expression patterns. We present Epigram, an analysis pipeline that predicts histone modification and DNA methylation patterns from DNA motifs. The identified cis-elements represent interactions with the site-specific DNA-binding factors that establish and maintain epigenomic modifications. We catalog the cis-elements in embryonic stem cells and four derived lineages and found numerous motifs that have location preference, such as at the center of H3K27ac or at the edges of H3K4me3 and H3K9me3, which provides mechanistic insight about the shaping of the epigenome. The Epigram pipeline and predictive motifs are at http://wanglab.ucsd.edu/star/epigram.

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Section: Resultssupporting

confidence: 93%

Predicting the human epigenome from DNA motifs

2014

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“…As a negative control, acetylation in DN thymocytes of Rag2 Ϫ/Ϫ mice was very low across all J␣ segments. Consistent with a previous study that analyzed an allele with a distinct and larger deletion of the TEA promoter region (25), acetylation in ⌬TEA Rϫ␤ was very low across the 5Ј portion of the J␣ array, but it recovered gradually, and it was elevated above the level in Rϫ␤ at J␣47 and several sites further 3Ј (Fig. 2).…”

Section: Resultssupporting

confidence: 91%

“…2). As reported previously (21,25), acetylation was high in Rϫ␤ at the most 5Ј J␣ segments, and it declined gradually toward the 3Ј end of the J␣ array. As a negative control, acetylation in DN thymocytes of Rag2 Ϫ/Ϫ mice was very low across all J␣ segments.…”

Section: Resultssupporting

confidence: 86%

Role for rearranged variable gene segments in directing secondary T cell receptor α recombination

Hawwari

Krangel

2007

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

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During the recombination of variable (V) and joining (J) gene segments at the T cell receptor ␣ locus, a V␣J␣ joint resulting from primary rearrangement can be replaced by subsequent rounds of secondary rearrangement that use progressively more 5 V␣ segments and progressively more 3 J␣ segments. To understand the mechanisms that target secondary T cell receptor ␣ recombination, we studied the behavior of a T cell receptor ␣ allele (HY␣) engineered to mimic a natural primary rearrangement of TRAV17 to J␣57. The introduced V␣J␣ segment was shown to provide chromatin accessibility to J␣ segments situated within several kilobases downstream and to suppress germ-line J␣ promoter activity and accessibility at greater distances. As a consequence, the V␣J␣ segment directed secondary recombination events to a subset of J␣ segments immediately downstream from the primary rearrangement. The data provide the mechanistic basis for a model of primary and secondary T cell receptor ␣ recombination in which recombination events progress in multiple small steps down the J␣ array. Expression of a functional T cell receptor (TCR)␤ protein leads to the development of CD4 ϩ CD8 ϩ double-positive (DP) thymocytes, which then rearrange the Tcra locus (2). Tcra locus rearrangement is unique in several respects. First, primary Tcra rearrangements use J␣ segments at the 5Ј end of the 65-kb J␣ array (3-6). Second, primary rearrangements can be replaced by secondary rearrangements that use progressively more 3Ј J␣ segments until a selectable ␣␤ TCR is generated (7-12). Third, rearrangement occurs on both alleles in a relatively synchronous manner without allelic exclusion (10,13,14). Rearrangement terminates by down-regulation of recombinase expression as a result of positive selection or by apoptosis if positive selection fails to occur (6,(15)(16)(17). Positive selection allows the development of CD4 ϩ CD8 Ϫ or CD4 Ϫ CD8 ϩ single-positive thymocytes, which then exit the thymus to the circulation. Although much is known about primary rearrangements, little is known about the mechanisms that control secondary rearrangements.Multiple regulatory elements are known to activate and control accessibility to the J␣ array (composed of 61 J␣ segments) in DP thymocytes. The Tcra enhancer (E␣) at the 3Ј end of the Tcra locus was shown by gene targeting to control all V␣-to-J␣ rearrangements and to maintain the J␣ array in an accessible state in DP thymocytes (18,19). However, E␣-dependent accessibility also requires the activation of germ-line promoters within the J␣ array. The T early ␣ (TEA) and J␣49 promoters were identified at the 5Ј end of the J␣ array and were shown to account for the majority of primary rearrangements (20,21). Rearrangements in mice lacking both promoters were substantially reduced across the entire 5Ј region, recovering to normal levels by J␣37 (21). Two models have been proposed to explain the targeting of primary and secondary rearrangements (6,13,20). The ''developmental windows'' model suggests that sequential activation o...

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“…Relative to ΔJ49Rxβ mice, histone acetylation was substantially reduced from the TEA exon through J α 48, but was substantially increased at multiple sites further 3′. Previous work had shown that TEA deletion reduced Tcra locus acetylation from TEA through J α 53 12 . The current data imply that the TEA and J α 49 promoters collaborate to maintain a normal amount of histone acetylation through J α 48.…”

Section: J α Chromatin Structure In Promoter-deleted Micementioning

confidence: 80%

Regulation of T cell receptor α gene assembly by a complex hierarchy of germline Jα promoters

2005

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Tcra gene assembly is characterized by an orderly progression of primary and secondary V α to J α recombination events across the J α array, but the targeting mechanisms responsible for this progression are largely unknown. Previous studies revealed that the TEA promoter plays an important role in targeting primary Tcra rearrangements. We show that TEA and a novel promoter associated with J α 49 target primary recombination to discrete sets of C α -distal J α segments and together direct nearly all normal primary recombination events. Further, we show that TEA promoter deletion activates previously suppressed downstream promoters and stimulates primary rearrangement to centrally located J α segments. Central promoter derepression also occurs following primary rearrangement, thereby providing a mechanism to target secondary recombination events. Tcra rearrangement has several unique features that are thought to increase the likelihood of positive selection 2 , 3 . First, V α to J α rearrangement occurs on both alleles without allelic exclusion. Second, initial, or primary rearrangements, are targeted to J α segments at C α -distal, or 5′ end, of the 70 kb J α array (polarity is denoted in reference to the sense strand throughout). If primary rearrangement fails to produce a selectable TCR, DP thymocytes may then undergo multiple additional rounds of secondary rearrangement that involve progressively more 5′ V α gene segments and progressively more 3′ J α gene segments. Moreover, the 5′ to 3′ progression along the J α array is nearly synchronous on two Tcra alleles. Tcra rearrangement is ultimately terminated by positive selection, which silences recombinase expression, or by cell death resulting from a lack of positive selection. Thus, secondary V α to J α rearrangement provides thymocytes multiple opportunities for positive selection, and is critical for the production of a robust and diverse TCRα repertoire 4 , 5 .The mechanisms that direct primary Tcra rearrangement are only partially understood. The Tcra enhancer (E α ), situated 3′ of C α , controls the entire J α array and is required for all V α to J α recombination events 6 . The T early α (TEA) promoter, located at the 5′ end of the J α array, acts more locally, and controls usage of the most 5' J α segments (J α 61-J α 53) 7 . However, TEAdeficient mice have quantitatively normal J α usage downstream of this region, suggesting the

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TEA regulates local TCR‐Jα accessibility through histone acetylation

Cited by 16 publications

References 27 publications

Predicting the human epigenome from DNA motifs

Predicting the human epigenome from DNA motifs

Role for rearranged variable gene segments in directing secondary T cell receptor α recombination

Regulation of T cell receptor α gene assembly by a complex hierarchy of germline Jα promoters

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