Early human IgH gene assembly in Epstein-Barr virus-transformed fetal B cell lines. Preferential utilization of the most JH-proximal D segment (DQ52) and two unusual VH-related rearrangements.

Nickerson, Katherine G.; Berman, Jeffrey E.; Glickman, Eva; Chess, Leonard; Alt, Frederick W.

doi:10.1084/jem.169.4.1391

Cited by 65 publications

(17 citation statements)

References 36 publications

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“…However, by the time the in utero gestational period was over, the D segment use shifted to the 5ЈV H proximal end of the locus, particularly increasing the frequencies of D2-2, D3-3, D3-10, and D6 -13 in full-term neonates and adults. Moreover, the finding that in the fetus the two most J H proximal D segments, D1-26 and D7-27, preferentially rearranged with J H 2 and J H 3 further supports the hypothesis that proximity of the D segment and J H pairing is favored in the V H DJ H rearrangement process in B lineage cells of the fetus (32,33). Even though reports suggested that the reason for fetal D7-27 pairing with 5ЈJ H segments was based on the D segment size (12,19), we consider this unlikely because other small D segments, such as the ones in the D4 family, were not frequently used, whereas the relatively long D1-26, which is the second most J H proximal D segment, also paired preferentially with 5ЈJ H segments.…”

Section: Discussionsupporting

confidence: 54%

Developmental Changes in the Human Heavy Chain CDR3

Souto-Carneiro

Sims

Girschik

et al. 2005

The Journal of Immunology

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The CDR3 of the Ig H chain (CDR3H) is significantly different in fetal and adult repertoires. To understand the mechanisms involved in the developmental changes in the CDR3H of Ig H chains, sets of nonproductive VHDJH rearrangements obtained from fetal, full-term neonates and adult single B cells were analyzed and compared with the corresponding productive repertoires. Analysis of the nonproductive repertoires was particularly informative in assessing developmental changes in the molecular mechanisms of VHDJH recombination because these rearrangements did not encode a protein and therefore their distribution was not affected by selection. Although a number of differences were noted, the major reasons that fetal B cells expressed Ig H chains with shorter CDR3H were both diminished TdT activity in the DJH junction and the preferential use of the short JH proximal D segment D7–27. The enhanced usage of D7–27 by fetal B cells appeared to relate to its position in the locus rather than its short length. The CDR3H progressively acquired a more adult phenotype during ontogeny. In fetal B cells, there was decreased recurrent DJH rearrangements before VH-DJH rearrangement and increased usage of junctional microhomologies both of which also converted to the adult pattern during ontogeny. Overall, these results indicate that the decreased length and complexity of the CDR3H of fetal B cells primarily reflect limited enzymatic modifications of the joins as well as a tendency to use proximal D and JH segments during DJH rearrangements.

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Section: Discussionsupporting

confidence: 54%

Developmental Changes in the Human Heavy Chain CDR3

Souto-Carneiro

Sims

Girschik

et al. 2005

The Journal of Immunology

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“…The existence of separate DH and JH chromatin domains may help repress recombination of V H to unrearranged DH gene segments. This organization may also explain the preferential targeting of the DFL16.1 and DQ52 segments in initial DJH rearrangements (32)(33)(34), because these segments would be located at the 5Ј extremity of each domain and hence potentially close to cis-acting chromatin regulatory elements. An increased use of DFL16.1 and a decreased frequency of JH3 and JH4 rearrangements were indeed observed in mice deleted for the DQ52 segment (35).…”

Section: Discussionmentioning

confidence: 99%

Activation of V(D)J Recombination at the IgH Chain JH Locus Occurs within a 6-Kilobase Chromatin Domain and Is Associated with Nucleosomal Remodeling

Maës

Chappaz

Cavelier

et al. 2006

The Journal of Immunology

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IgH genes are assembled during early B cell development by a series of regulated DNA recombination reactions in which DH and JH segments are first joined followed by VH to DJH rearrangement. Recent studies have highlighted the role of chromatin structure in the control of V(D)J recombination. In this study, we show that, in murine pro-B cell precursors, the JH segments are located within a 6-kb DNase I-sensitive chromatin domain containing acetylated histones H3 and H4, which is delimited 5′ by the DQ52 promoter element and 3′ by the intronic enhancer. Within this domain, the JH segments are covered by phased nucleosomes. High-resolution mapping of nucleosomes reveals that, in pro-B cells, unlike recombination refractory nonlymphoid cells, the recombination signal sequences flanking the four JH segments are located in regions of enhanced micrococcal nuclease and restriction enzyme accessibility, corresponding to either nucleosome-free regions or DNA rendered accessible within a nucleosome. These results support the idea that nucleosome remodeling provides an additional level of control in the regulation of Ig locus accessibility to recombination factors in B cell precursors.

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“…In the human system, DHQ52-J 1 joining was frequently observed in Epstein-Barr virus-transformed fetal B cell lines (23).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the immunoglobulin heavy chain complementarity determining region (CDR)-III sequences from human B cell precursor acute lymphoblastic leukemia cells.

Kiyoi¹,

Naoe²,

Horibe³

et al. 1992

J. Clin. Invest.

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Sequence analysis of the immunoglobulin heavy chain complementarity determining region (CDR)-III of B-lineage cells at various stages has provided important insights concerning B cell maturation and selection. Knowledge of human CDR-III sequences has been relatively limited compared with that of the murine system. We analyzed the CDR-III sequences of B cell precursor acute lymphoblastic leukemia (pre-B ALL) cells in 23 newly diagnosed and 10 relapsed patients, in order to elucidate the organization of CDR-III in B cell precursors. We found a very low frequency of somatic mutations in D and JH regions, preferential use of DLR, Dxp, DHQS2, and DN elements, and of 3' side JH segments, and no predominant usage of D coding frames. Unusual joinings such as VH-D-D-JH and VH_ JH were observed in three, and one sequences, respectively. We compared the CDR-III sequences derived from 10 patients between diagnosis and relapse. Two of them had three spots of mutated nucleotides at relapse, all of which were found in the N region near the D segments. Our data showed the possibility of somatic mutation at relapse, in addition to developmentally regulated rearrangement of the immunoglobulin gene at the stage of B cell precursors. (J. Clin. Invest. 1992. 89:739-746.)

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Early human IgH gene assembly in Epstein-Barr virus-transformed fetal B cell lines. Preferential utilization of the most JH-proximal D segment (DQ52) and two unusual VH-related rearrangements.

Cited by 65 publications

References 36 publications

Developmental Changes in the Human Heavy Chain CDR3

Developmental Changes in the Human Heavy Chain CDR3

Activation of V(D)J Recombination at the IgH Chain JH Locus Occurs within a 6-Kilobase Chromatin Domain and Is Associated with Nucleosomal Remodeling

Characterization of the immunoglobulin heavy chain complementarity determining region (CDR)-III sequences from human B cell precursor acute lymphoblastic leukemia cells.

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