Important Roles for E Protein Binding Sites within the Immunoglobulin κ Chain Intronic Enhancer in Activating Vκ Jκ
 Rearrangement

Inlay, Matthew A.; Hua, Tian; Lin, Tongxiang; Xu, Yiming

doi:10.1084/jem.20041135

Cited by 71 publications

(81 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The previous studies have demonstrated the functional importance of iEk and 39Ek enhancers in Igk rearrangement during B cell development in vivo (6,16,38). Targeted mutation of the E2A-binding motifs in iEk impairs Igk rearrangement (16), directly demonstrating the crucial functions of E2A and iEk in Igk rearrangement in vivo.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

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: Discussionmentioning

confidence: 99%

“…In addition, Vk genes also contain E-boxes in their promoters and in close proximity to RSSs (12)(13)(14)(15). Moreover, targeted mutation of the E-boxes, E1 and E2, in iEk impairs Igk rearrangement (16), directly demonstrating the functional importance of E-proteins in Igk rearrangement during B cell development in vivo.…”

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Ig V(D)J gene rearrangement is controlled by STAT5, Pax5 and YY1, whereas IgL VJ gene rearrangement is regulated by the E2A proteins [10,19,20,21,22,23]. The E2A proteins interact directly with binding sites present in the IgK light chain gene enhancer to modulate IgK VJ gene rearrangement [24]. Furthermore, in the presence of self-reactivity they promote receptor editing [25].…”

Section: Developmental-specific Regulation Of Antigen Receptor Gene Amentioning

confidence: 99%

Epigenetics of antigen-receptor gene assembly

Murre

2007

Current Opinion in Genetics & Development

View full text Add to dashboard Cite

IntroductionIt is established that the temporal and lineage specificity of V(D)J rearrangement is controlled at multiple levels [1,2]. These include germ-line transcription, chromatin remodeling, histone acetylation and DNA methylation. It is, however, unknown how a region spanning large genomic distances allows the assembly of antigen receptor genes. Recent data have suggested that an underlying structural order must exist that facilitates the association of DNA elements separated by large genomic distances. B cell development and ordered immunoglobulin gene rearrangementThe developmental progression of B cells has been characterized on the basis of antigen receptor gene rearrangements and on the dynamic expression patterns of cell surface proteins, which have served as maturation markers [3]. The Igh locus is comprised of distinct DNA elements encoding the variable (V), diversity (D), joining (J), and constant (C) regions. Eight Igh constant regions encode for distinct isotypes that include C μ , C δ , C γ1 C γ2a , C γ2b , C γ3 , C α and C ε . Upstream of the IgM constant region are located twelve D H and four J H segments. Fifteen partially dispersed V region families are present that span approximately 2 Mbp of genomic sequence. The IgK and L light chain loci are also organized into distinct DNA elements, encoding V H , J H and C H segments. Ig V H , D H and J H elements are flanked by recombination signal sequences that interact with the RAG1 and RAG2 gene products.In pro-B cells, Igh D H J H joining precedes that of V H (D H )J H gene rearrangement [4]. Once a V(D)J gene rearrangement leads to a productive joint, pre-BCR signaling acts to inhibit RAG1 and RAG2 gene expression and to promote the survival, expansion and developmental progression of large pre-B cells [5.6]. The expansion phase is followed by cell cycle arrest, during which RAG gene expression is reactivated to initiate the rearrangement of the Ig light chain genes. In the presence of self-reactivity, continued rearrangements will replace primary IgK VJ joints, generating receptors with novel specificities. Once a BCR is expressed which lacks auto-reactivity, tonic signaling mediated by the BCR will permanently suppress RAG1 and RAG2 gene expression. Tonic BCR signaling will also trigger the migration of B cells to the peripheral lymphoid organs where they, upon interacting with pathogens, will undergo class switching and somatic hypermutation. T-lineage development and T cell receptor gene rearrangementT-lineage cells also develop sequentially [7]. Two distinct T cell lineages develop from a common progenitor, named αβ and γδ T cells. The rearrangement of the TCRβ and γδ loci is Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production...

show abstract

“…14 14 However, this particular kB-binding site was not essential for rearrangement in vivo. 15 This does not rule out a redundant role for this site nor does it exclude a contribution of NF-kB at other sites. The most notable experiment supporting a role for NF-kB in demethylation utilized v-Abl-transformed pre-B-like cells.…”

mentioning

confidence: 99%