Localized Gene-Specific Induction of Accessibility to V(D)j Recombination Induced by E2a and Early B Cell Factor in Nonlymphoid Cells

Goebel, Peter; Janney, Noel; Valenzuela, Joaquín R.; Romanow, William J.; Murre, Cornelis; Feeney, Ann J.

doi:10.1084/jem.194.5.645

Cited by 93 publications

(76 citation statements)

References 45 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, we showed that E2A has the ability to bind directly to the conserved E-box site present downstream of Vk RSSs and to increase histone acetylation at these regions in BOSC23 cells, supporting the notion that the critical function of E2A to induce recombination might be to induce the local accessibility of rearranging gene segments by recruiting HAT complexes rather than to induce transcription itself. Furthermore, the observation that E2A directly binds to the promoter and RSS regions of the VkI gene family members may explain how E2A could induce localized genespecific accessibility, which was reported previously (43).…”

Section: Discussionsupporting

confidence: 57%

E2A and CBP/p300 Act in Synergy To Promote Chromatin Accessibility of the Immunoglobulin κ Locus

Sakamoto

Wakae

Anzai

et al. 2012

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

V(D)J recombination of Ig and TCR genes is strictly regulated in a lineage- and stage-specific manner by the accessibility of target gene chromatin to the recombinases RAG1 and RAG2. It has been shown that enforced expression of the basic helix–loop–helix protein, E2A, together with RAG1/2 in a nonlymphoid cell line BOSC23 can induce V(D)J recombination in endogenous Igκ and TCR loci by increasing chromatin accessibility of target gene segments. In this study, we demonstrate that ectopically expressed E2A proteins in BOSC23 cells have the ability to bind directly to the promoter and recombination signal sequence of Vκ genes and to recruit histone acetyltransferase CBP/p300. Overexpression of CBP/p300 in conjunction with E2A results in enhancement of E2A-induced histone acetylation, germline transcription, and Igκ rearrangement. Conversely, knockdown of endogenous CBP/p300 expression by small interfering RNA leads to a decrease in histone acetylation, germline transcription and Igκ rearrangement. Furthermore, analyses using a mouse pre-B cell line revealed that endogenous E2A proteins also bind to a distinct set of Vκ genes and regulatory regions in the mouse Igκ locus and act to increase histone acetylation by recruiting p300, confirming the similar findings observed with BOSC23 cells. These observations indicate that E2A plays critical roles in inducing Igκ rearrangement by directly binding to and increasing chromatin accessibility at target gene segments.

show abstract

Section: Discussionsupporting

confidence: 57%

E2A and CBP/p300 Act in Synergy To Promote Chromatin Accessibility of the Immunoglobulin κ Locus

Sakamoto

Wakae

Anzai

et al. 2012

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Evidence for prolonged light-chain recombination in our series is also provided by the increased usage of more IGKJ-distal genes in IGKV-KDE versus IGKV-J rearrangements (especially in λ-CLL). This may be attributed to a shift in accessibility to the recombinase from the J-proximal to the J-distal parts of the IGK locus at more advanced stages in B-cell ontogeny (54,55).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Expressed and Non-Expressed IGK Locus Rearrangements in Chronic Lymphocytic Leukemia

Belessi

Stamatopoulos

Hadzidimitriou

et al. 2005

Mol Med

View full text Add to dashboard Cite

Immunoglobulin κ (IGK) locus rearrangements were analyzed in parallel on cDNA/genomic DNA in 188 κ-and 103 λ-chronic lymphocytic leukemia (CLL) cases. IGKV-KDE and IGKJ-C-intron-KDE rearrangements were also analyzed on genomic DNA. In κ-CLL, only 3 of 188 cases carried double in-frame IGKV-J transcripts: in such cases, the possibility that leukemic cells expressed more than one κ chain cannot be excluded. Twenty-eight κ-CLL cases also carried nonexpressed (nontranscribed and/or outof-frame) IGKV-J rearrangements. Taking IGKV-J, IGKV-KDE, and IGKJ-C-intron-KDE rearrangements together, 38% of κ-CLL cases carried biallelic IGK locus rearrangements. In λ-CLL, 69 IGKV-J rearrangements were detected in 64 of 103 cases (62%); 24 rearrangements (38.2%) were in-frame. Four cases carried in-frame IGKV-J transcripts but retained monotypic light-chain expression, suggesting posttranscriptional regulation of allelic exclusion. In all, taking IGKV-J, IGKV-KDE, and IGKJ-C-intron-KDE rearrangements together, 97% of λ-CLL cases had at least 1 rearranged IGK allele, in keeping with normal cells. IG repertoire comparisons in κ-versus λ-CLL revealed that CLL precursor cells tried many rearrangements on the same IGK allele before they became λ producers. Thirteen of 28 and 26 of 69 non-expressed sequences in, respectively, κ-or λ-CLL had < 100% homology to germline. This finding might be considered as evidence for secondary rearrangements occurring after the onset of somatic hypermutation, at least in some cases. The inactivation of potentially functional IGKV-J joints by secondary rearrangements indicates active receptor editing in CLL and provides further evidence for the role of antigen in CLL immunopathogenesis.

show abstract

“…Ectopic expression of E2A in non-B cells was also found to induce germ-line Ig transcription and rearrangement, suggesting that E2A might play a key role in Ig gene regulation (19)(20)(21). More recent studies demonstrated that transfection of the kidney cell line BOSC23 with E2A and the RAG recombination machinery was sufficient to drive diverse recombination events at the Ig heavy and light chain loci (22,23). Overexpression studies have also implicated E2A in the regulation of other genes involved in the initiation and maintenance of the B cell developmental program.…”

mentioning

confidence: 99%

Identification of E2A target genes in B lymphocyte development by using a gene tagging-based chromatin immunoprecipitation system

Greenbaum

Zhuang

2002

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

View full text Add to dashboard Cite

The transcription factors encoded by the E2A gene are known to be essential for B lymphocyte development, and ectopic expression or gene inactivation studies have revealed several potential lineagespecific E2A target genes. However, it remains unknown whether these target genes are directly regulated by E2A at the transcriptional level. We therefore generated mice carrying an affinity-tagged E2A knock-in allele to provide a system for the direct elucidation of E2A target genes based on E2A binding to target regulatory regions. Abelson-transformed pre-B cell lines derived from these mice were used in chromatin immunoprecipitation experiments to identify regulatory sequences bound by E2A in the context of an early B lymphocyte environment. Significant E2A binding was detected at the promoters and enhancers of several essential B-lineage genes, including the Ig intronic and 3 enhancers, 5 and VpreB surrogate light chain promoters, the EBF locus promoter region, and the mb-1 (Ig␣) promoter. Low levels of E2A binding were observed at several other lymphoid-restricted regulatory regions including the Ig heavy chain (IgH) intronic enhancer, the IgH 3 enhancers hs3b͞hs4, the RAG-2 enhancer, and the 5 regions of the B29 and TdT loci. An E2A target gene, the predicted butyrophilin-like gene NG9 (BTL-II), was also identified by using a chromatin immunoprecipitation-based cloning strategy. In summary, our studies have provided evidence that E2A is directly involved in the transcriptional regulation of a number of early B-lineage genes.T he development of lymphocytes from hematopoietic stem cells involves a series of highly regulated differentiation events that depend on the collaborative efforts of a number of transcription factors. These transcription factors coordinately regulate lymphopoiesis through the initiation, maintenance, and restriction of lineage-specific gene expression programs. The transcription factors encoded by the E2A gene are known to play critical roles in the regulation of lymphocyte development. E2A proteins are highly expressed in developing lymphoid cells (1, 2), and gene targeting studies have shown that E2A proteins are required for the initiation of B cell development in the bone marrow. Mice deficient in E2A demonstrate a complete and persistent block at the earliest stage of B cell development before the initiation of Ig heavy chain gene rearrangements, as well as a dramatic reduction in thymocyte number (3, 4).The mammalian E2A gene encodes two major products, E12 and E47, which are members of the basic helix-loop-helix (bHLH) family of transcription factors (5, 6). bHLH proteins are characterized by a conserved HLH dimerization domain and an adjacent basic region that mediates DNA binding (7,8). E12 and E47 are generated by alternative splicing of adjacent exons encoding their bHLH domains and bind the consensus E-box sequence CANNTG as homodimers or as heterodimers with other bHLH transcription factors (5-7, 9, 10). As E-box binding factors, E12 and E47 are members of a subfamily of bHLH tra...

show abstract

Localized Gene-Specific Induction of Accessibility to V(D)j Recombination Induced by E2a and Early B Cell Factor in Nonlymphoid Cells

Cited by 93 publications

References 45 publications

E2A and CBP/p300 Act in Synergy To Promote Chromatin Accessibility of the Immunoglobulin κ Locus

E2A and CBP/p300 Act in Synergy To Promote Chromatin Accessibility of the Immunoglobulin κ Locus

Analysis of Expressed and Non-Expressed IGK Locus Rearrangements in Chronic Lymphocytic Leukemia

Identification of E2A target genes in B lymphocyte development by using a gene tagging-based chromatin immunoprecipitation system

Contact Info

Product

Resources

About