A Stage-Specific Enhancer of Immunoglobulin J Chain Gene Is Induced by Interleukin-2 in a Presecretor B Cell Stage
40
Citation
41
Reference
10
Related Paper
Citation Trend
Keywords:
Enhancer RNAs
J chain
STAT5
Immunoglobulin heavy chain
Enhancer sequences are regulatory regions that greatly increase transcription of certain eukaryotic genes. An immunoglobulin heavy-chain variable gene segment is moved from a region lacking enhancer activity to a position adjacent to the known heavy-chain enhancer early in B-cell maturation. In lymphoid cells, the heavy-chain and SV40 enhancers bind a common factor essential for enhancer function. In contrast, fibroblast cells contain a functionally distinct factor that is used by the SV40 but not by the heavy-chain enhancer. The existence of different factors in these cells may explain the previously described lymphoid cell specificity of the heavy-chain enhancer.
Immunoglobulin heavy chain
Enhancer RNAs
Heavy chain
Cite
Citations (271)
Abstract To execute different biological functions, the expression pattern of immunoglobulin heavy chain genes (IgH) is altered during B lymphocyte differentiation. Early in B cell differentiation, it is assumed that the heavy chain promoter and the intragenic enhancer (Eμ) ensure VDJ recombination. This leads to the expression of the immunoglobulin receptor on the cell surface. An additional strong enhancer in the far 3′ end of the IgH locus has, however, prompted a re‐evaluation of the regulation of immunoglobulin gene expression. To define the temporal and spatial regulation of the IgH 3′ enhancer, transgenic mice harboring an enhancerdependent reporter gene construct were generated. Here we demonstrate that IgH 3′ enhancer activity is largely restricted to activated immunocompetent B cells. Furthermore, the enhancer can be transactivated following mitogen stimulation with lipopolysaccharide and 12‐O‐tetradecanylphorbol 13‐acetate. We propose a model whereby 3′ enhancer activation is linked to the activation of resting immunocompetant B cells. The implications of the enhancer being active in late B lymphocyte differentiation, when heavy chain class switching occurs, are discussed.
Immunoglobulin heavy chain
Heavy chain
Cite
Citations (55)
The enhancer for the immunoglobulin mu heavy chain gene (IgH) activates a heterologous gene at the pre-B cell stage of B lymphocyte differentiation. A lymphoid-specific element, microB, is necessary for enhancer function in pre-B cells. A microB binding protein is encoded by the PU.1/Spi-1 proto-oncogene. Another sequence element, microA, was identified in the mu enhancer that binds the product of the ets-1 proto-oncogene. The microA motif was required for microB-dependent enhancer activity, which suggests that a minimal B cell-specific enhancer is composed of both the PU.1 and Ets-1 binding sites. Co-expression of both PU.1 and Ets-1 in nonlymphoid cells trans-activated reporter plasmids that contained the minimal mu enhancer. These results implicate two members of the Ets family in the activation of IgH gene expression.
Enhancer RNAs
Immunoglobulin heavy chain
Enhancer trap
Heterologous
Cite
Citations (229)
The transcription of immunoglobulin genes is controlled by variable region promoters and by enhancers, both of which are lymphoid specific. Because immunoglobulin genes are subject to an extremely complex regulation, we anticipated that there might be additional control elements for these genes. We therefore sought additional enhancers and demonstrate here that there is indeed another weak transcriptional enhancer just 3' to the mouse alpha constant region. This novel immunoglobulin enhancer is lymphoid specific and at two positions can bind members of the Oct family of transcription factors.
Immunoglobulin heavy chain
Enhancer RNAs
Immunoglobulin gene
Transcription
Locus control region
Cite
Citations (50)
The immunoglobulin heavy-chain (IgH) enhancer serves to activate efficient and accurate transcription of cloned IgH genes when introduced into B lymphomas or myelomas. The role of this enhancer after gene activation, however, is unclear. The endogenous IgH genes in several cell lines, for example, have lost the IgH enhancer by deletion and yet continue to be expressed. This might be explained if the role of the enhancer were to establish high-level gene transcription but not to maintain it. Alternatively, other enhancers might lie adjacent to endogenous IgH genes, substituting their activity for that of the lost IgH enhancer. To address both of these alternatives, we searched for enhancer activity within the flanking regions of one of these IgH enhancer-independent genes and designed an experiment that allowed us to consider separately the establishment and maintenance of expression of a transfected gene. For the latter experiment we generated numerous pre-B cell lines stably transformed with a gamma 2a gene. In this gene, the IgH enhancer lay at a site outside the heavy-chain transcription unit, between DH and JH gene segments. After expression of the transfected gene was established, selective conditions were chosen for the outgrowth of subclones that had undergone D-J joining and thus IgH enhancer deletion. Measurements of gamma 2a expression before and after enhancer deletion revealed that the enhancer was required for maintenance of expression of the transfected gene. The implication of this finding for models of enhancer function in endogenous genes is discussed.
Enhancer RNAs
Immunoglobulin heavy chain
Enhancer trap
Immunoglobulin gene
Transcription
Cite
Citations (6)
Enhancer RNAs
J chain
STAT5
Immunoglobulin heavy chain
Cite
Citations (40)
The immunoglobulin heavy-chain (IgH) enhancer serves to activate efficient and accurate transcription of cloned IgH genes when introduced into B lymphomas or myelomas. The role of this enhancer after gene activation, however, is unclear. The endogenous IgH genes in several cell lines, for example, have lost the IgH enhancer by deletion and yet continue to be expressed. This might be explained if the role of the enhancer were to establish high-level gene transcription but not to maintain it. Alternatively, other enhancers might lie adjacent to endogenous IgH genes, substituting their activity for that of the lost IgH enhancer. To address both of these alternatives, we searched for enhancer activity within the flanking regions of one of these IgH enhancer-independent genes and designed an experiment that allowed us to consider separately the establishment and maintenance of expression of a transfected gene. For the latter experiment we generated numerous pre-B cell lines stably transformed with a gamma 2a gene. In this gene, the IgH enhancer lay at a site outside the heavy-chain transcription unit, between DH and JH gene segments. After expression of the transfected gene was established, selective conditions were chosen for the outgrowth of subclones that had undergone D-J joining and thus IgH enhancer deletion. Measurements of gamma 2a expression before and after enhancer deletion revealed that the enhancer was required for maintenance of expression of the transfected gene. The implication of this finding for models of enhancer function in endogenous genes is discussed.
Enhancer RNAs
Immunoglobulin heavy chain
Enhancer trap
Immunoglobulin gene
Transcription
Cite
Citations (13)
Immunoglobulin heavy chain
Enhancer RNAs
Locus control region
Cite
Citations (50)
Abstract CD4+ T cells differentiate in response to specific cytokine environments that induce the activation of STAT transcription factors and, ultimately, cell-specific gene profiles. The differentiation of TH2 cells requires the cytokines IL-4 and IL-2, which signal via the activation of STAT6 and STAT5, respectively. Interestingly, signaling via the IL-2/STAT5 axis is also required for the differentiation of the TH1 cell type. Our lab recently found that IL-2 signaling induces expression of the Ikaros Zinc Finger (IkZF) transcription factor Eos (Ikzf4) in TH1 cells, and that Eos positively regulates TH1-specific gene expression. Given the requirement for IL-2 signaling in TH2 development, we hypothesized that Eos may also play a role in TH2 differentiation. Indeed, we found that Eos expression was increased in TH2 cells at both the transcript and protein level as compared to TH0, TH1, and TFH-like cells. We also found that Eos knockdown resulted in a significant decrease in the expression of the canonical TH2 genes Il4 and Il13. When we cultured Eos-deficient cells in TH2-polarizing conditions, we similarly observed a decrease in Il4 and Il13 expression, as well as reduced expression of Il2ra and Il2rb. Eos-deficient TH2 cells also displayed decreased expression of Prdm1, the gene encoding Blimp-1, which represses the expression of alternative T helper cell gene programs in TH2 cells. Taken together, these data support a novel, positive role for Eos in the regulation of the TH2 gene program.
STAT5
STAT6
Cite
Citations (0)
Immunoglobulin heavy chain
Enhancer RNAs
Transcription
Immunoglobulin gene
Cite
Citations (85)