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Allelic Exclusion Β Associated with TCR Chromatin Β a Change in The A Change in the Structure of Vβ Chromatin Associated with TCR β Allelic Exclusion Rajkamal Tripathi, Annette Jackson and Michael S. Krangel This information is current as J Immunol 2002; 168:2316-2324; ; of September 28, 2021. doi: 10.4049/jimmunol.168.5.2316 http://www.jimmunol.org/content/168/5/2316 Downloaded from References This article cites 69 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/168/5/2316.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. A Change in the Structure of V␤ Chromatin Associated with TCR ␤ Allelic Exclusion1 Rajkamal Tripathi, Annette Jackson, and Michael S. Krangel2 To investigate chromatin control of TCR ␤ rearrangement and allelic exclusion, we analyzed TCR ␤ chromatin structure in double negative (DN) thymocytes, which are permissive for TCR ␤ recombination, and in double positive (DP) thymocytes, which are postallelic exclusion and nonpermissive for V␤ to D␤J␤ recombination. Histone acetylation mapping and DNase I sensitivity studies indicate V␤ and D␤J␤ segments to be hyperacetylated and accessible in DN thymocytes. However, they are separated from each other by hypoacetylated and inaccessible trypsinogen chromatin. The transition from DN to DP is accompanied by selective down-regulation of V␤ acetylation and accessibility. The level of DP acetylation and accessibility is minimal for five of six V␤ segments studied but remains substantial for one. Hence, the observed changes in V␤ chromatin structure appear sufficient to account for allelic exclusion of many V␤ segments. They may contribute to, but not by themselves fully account for, allelic Downloaded from exclusion of others. The Journal of Immunology, 2002, 168: 2316–2324. uring T and B lymphocyte development, TCR and Ig on the assembly of a membrane Ig␮ polypeptide into a pre-B cell gene variable (V), diversity (D), and joining (J) seg- receptor (BCR) complex (12, 13). Pre-TCR and pre-BCR signaling D ments are assembled by the process of V(D)J recombi- also induces critical developmental transitions during T and B nation (1, 2). In both lineages, V(D)J recombination occurs in a lymphocyte development (from DN to DP and pro-B to pre-B, http://www.jimmunol.org/ highly ordered and tightly regulated fashion (3–6). In the B lin- respectively), as well as the proliferative expansion of developing eage, IgH locus rearrangement initiates in pro-B cells and occurs lymphocytes (14, 15). How pre-TCR- and pre-BCR-derived sig- in two steps, first DH to JH, and then VH to DJH. Rearrangement of nals impact the process of V(D)J recombination to inhibit V to DJ Ig L chain loci (Ig␬ and Ig␭) initiates subsequently, at the pre-B rearrangement at the TCR ␤ and IgH loci is not well understood. cell stage, and occurs in a single step (V␬ to J␬ or V␭ to J␭). In V(D)J recombination is initiated by the recombinase-activating similar fashion, V(D)J recombination occurs at two distinct stages gene (RAG)-1 and RAG-2 proteins, which introduce double-strand in the development of ␣␤ T lineage cells. TCR ␤ locus rearrange- breaks at recombination signal sequences (RSSs) flanking Ig and Ϫ Ϫ ment initiates in CD4 CD8 double negative (DN)3 thymocytes TCR gene segments (1, 2). One level at which V(D)J recombina- and occurs in two steps, first D␤ to J␤ and then V␤ to DJ␤. TCR tion can be regulated is by developmental activation and inactiva- by guest on September 28, 2021 ϩ ϩ ␣ locus rearrangement initiates subsequently in CD4 CD8 tion of RAG gene expression. For example, developmental inac- double positive (DP) thymocytes and occurs in a single step tivation of RAG gene expression can account for the termination (V␣ to J␣). of V␣ to J␣ rearrangement upon transition of DP thymocytes to the A striking regulatory feature of V(D)J recombination is the phe- single positive stage, and for termination of Ig L chain rearrange- nomenon of allelic exclusion, which restricts precursor lympho- ment on transition of pre-B cells to the immature B cell stage (6, cytes to the production of a single, functional Ag receptor gene at 16). However, other developmental changes in V(D)J recombina- a given locus. Allelic exclusion functions in highly analogous fash- tion can occur in the face of ongoing RAG gene expression and ion at the IgH and TCR ␤ loci. In each case, the presence of a ␤ ␤ recombinase activity. The inhibition of V to DJ and VH to DJH functional VDJ rearrangement on one allele inhibits the V to DJ rearrangement that characterizes allelic exclusion falls into this step of rearrangement on the second allele by a feedback mecha- category. Although pre-TCR and pre-BCR signaling down-regu- nism (7–9). For TCR ␤, the feedback signal depends on the as- lates RAG expression in late-stage DN thymocytes and pro-B sembly of a TCR ␤ polypeptide into a pre-TCR complex with cells, respectively, allelic exclusion is enforced despite the subse- pre-T␣ and CD3, and on the activity of the nonreceptor protein quent up-regulation of RAG expression that is associated with V␣ tyrosine kinase lck (10, 11). Similarly, for IgH this signal depends to J␣ rearrangement in DP thymocytes, and with V␬ to J␬ and V␭ to J␭ rearrangement in pre-B cells (6, 16). In general, develop- Department of Immunology, Duke University Medical Center, Durham, NC 27710 mental changes in recombinase targeting have been attributed to Received for publication November 9, 2001. Accepted for publication December developmental changes in locus accessibility to the recombinase, 21, 2001. with chromatin structure under the control of specific promoters The costs of publication of this article were defrayed in part by the payment of page and enhancers (3–6, 17–19). However, data addressing the role of charges. This article must therefore be hereby marked advertisement in accordance chromatin structure in the process of allelic exclusion have been with 18 U.S.C. Section 1734 solely to indicate this fact. 1 limited (20). This work was supported by National Institutes of Health Grants GM41052 and ␤ Ј AI49934. The TCR locus spans roughly 700 kb (21). At the 3 end are ␤ ␤ ␤ ␤ 2 Address correspondence and reprint requests to Dr. Michael S. Krangel, Department two D -J -C clusters, as well as a single, inverted V gene of Immunology, Duke University Medical Center, PO Box 3010, Durham, NC 27710. segment. The majority of V␤ segments are scattered across a re- E-mail address: [email protected] gion that extends from 250 to 500 kb upstream of the D␤-J␤-C␤ 3 Abbreviations used in this paper: DN, double negative; DP, double positive; clusters. This V␤ domain is flanked on the 5Ј side and, remarkably, ␣AcH3, anti-diacetylated histone H3; BCR, B cell receptor; CHIP, chromatin immu- Ј noprecipitation; RAG, recombinase-activating gene; RSS, recombination signal se- on the 3 side as well, by extended arrays of trypsinogen genes and quence; B, bound; U, unbound. gene fragments. Moreover, one V␤ segment is located upstream of Copyright © 2002 by The American Association of Immunologists 0022-1767/02/$02.00 The Journal of Immunology 2317 the 5Ј trypsinogen cluster, ϳ650 kb away from the D␤-J␤-C␤ 0.7% agarose, transferred to nylon, and assayed by hybridization with 32P- clusters. To date, V(D)J recombination at the TCR ␤ locus has labeled probes generated by random priming. DNA fragments D␤J␤ ␤ (MMAE00665 153,405–153,996), T4T5 (MMAE00663 92,771–93,461), been shown to depend on two cis-elements. E , situated down- ␤ ␤ ␤ ␤ ␤ ␤ ␤ V 11 (MMAE00664 23,621–24,290), V 12 (MMAE00664 14,657– stream of C 2, is required for all D to J and V to DJ rear- 15,446), and V␤13 (MMAE00664 7,916–8,370) were produced by PCR. rangement events (22, 23), whereas a germline promoter (PD␤1), Hybridization was quantified using a PhosphorImager. situated upstream of D␤1, is required specifically for rearrange- ment events involving the D␤1-J␤1 cluster (24, 25). Thus, E␤ and Results PD␤1 cooperate to promote rearrangement of D␤1 and J␤1 seg- Strategy ments, but the extent to which this regulation occurs at the level of Acetylation is structural modification of the amino-terminal tails of accessibility, vs at a later step in the reaction, is not fully resolved core histones that is associated with an open, nuclease-sensitive (24–27). chromatin configuration (33–37). A variety of approaches have TCR ␤ allelic exclusion appears not to involve a developmental recently established a very tight relationship between histone hy- transition involving D␤-J␤-C␤ chromatin and the activities of E␤ peracetylation and accessibility for V(D)J recombination (18, 19, and PD␤1. First, signal ends associated with D␤ to J␤ rearrange- 27, 30, 38–42). Based on these results, we used acetylation map- ment are present even in DP thymocytes, suggesting that these ping in the current study to evaluate changes in the structure of segments maintain accessibility to the recombinase at this stage TCR ␤ locus chromatin that might be associated with TCR ␤ al- Ϫ Ϫ (24).
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