scholarly journals The role of CTCF binding sites in the 3′ immunoglobulin heavy chain regulatory region

2012 ◽  
Vol 3 ◽  
Author(s):  
Barbara K. Birshtein
Keyword(s):  
Heavy Chain ◽  
Binding Sites ◽  
Regulatory Region ◽  
Immunoglobulin Heavy Chain ◽  
Ctcf Binding

Immunoglobulin heavy-chain enhancer is required to maintain transfected gamma 2A gene expression in a pre-B-cell line

1990 ◽  
Vol 10 (3) ◽  
pp. 1076-1083
Author(s):  
B Porton ◽  
D M Zaller ◽  
R Lieberson ◽  
L A Eckhardt
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Heavy Chain ◽  
Gene Activation ◽  
Immunoglobulin Heavy Chain ◽  
Transcription Unit ◽  
Enhancer Activity ◽  
Igh Genes ◽  
High Level

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.

Unremitting Presence of Marrow Immunoglobulin Heavy Chain Gene Rearrangement (IGH-GR) 3 Months Following Autotransplant Is Associated with Poor Outcome in Disease Control in Patients with Multiple Myeloma (MM).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1807-1807
Author(s):  
Choon Kee Lee ◽  
Qi Wei ◽  
Mark Lovell ◽  
Karen Swisshelm ◽  
John Ryder ◽  
...  
Keyword(s):  
Disease Control ◽  
Heavy Chain ◽  
Gene Rearrangement ◽  
Immunoglobulin Heavy Chain ◽  
Pcr Primers ◽  
Chain Gene ◽  
High Dose ◽  
Cumulative Index ◽  
Post Transplant

Abstract Abstract 1807 Poster Board I-833 In the study, we sought to determine the role of serial monitoring of immunoglobulin heavy chain monoclonality by IGH-GR tests in symptomatic MM patients who have been uniformly treated with induction chemotherapy, autotransplant following high-dose melphalan-based ablative therapy and post-transplant maintenance. Between September 2006 and April 2009, 51 patients (median age 60, range 37 – 77 years) were evaluated for conventional cytogenetics, myeloma FISH panel and IGH-GR on bone marrow samples prospectively every 3 months (mo) starting before initiation of therapy. The myeloma FISH panel included probes for chromosomes 1, 4, 11, 13, 14, and 17. IGH-GR test was performed by the InVivoScribe Technologies IGH Gene Rearrangement Assay using PCR primers targeting the conserved framework within the V-J region and J regions. A segment of the HLA-DQA1 gene was amplified as a control for patient DNA quality. 22 patients had IgG, 12 IgA, 13 light chain only and 4 nonsecretory MM. 30 patients (59%) were previously treated before and 16 (31%) had prior relapse. 23 patients (45%) received a tandem transplant and all patients received a maintenance regimen that included bortezomib and lenalidomide. Of the 51 patients, 11 (22%) had pre-therapy cytogenetic abnormalities (CA), 22 (43%) FISH abnormalities (FA) and 22 (43%) positive IGH-GR for monoclonality. Detection of positive IGH-GR was not associated with either CA (Fisher's exact test, p = 0.32) or FA (p = 0.14). The 3-year overall survival was 92% with 4 deaths. Relapse occurred in 10 with a 3-year cumulative index (CI) of 20%. In 3 to 12 mo following the first transplant, CA were seen in 7 (14% - 3 mo), 4 (8% - 6 mo) and 3 patients (6% - 12 mo); for FA, 9 (18%), 5 (10%) and 4 (8%); for IGH-GR, 10 (20%), 6 (12%) and 8 (17%). Findings before therapy were prognostic in survival and disease control. The 3-yr Kaplan-Meier survival was 80% for 11 patients (22%) with pre-therapy CA compared to 96% for those (n = 40) without CA (Logrank p = 0.02), 83% for 22 patients with FA (43%) compared to 100% for those (n = 29) without FA (p = 0.03), and 87% for 22 positive for IGH-GR (43%) versus 96% for those (n = 29) negative for IGH-GR (p = 0.03). Pre-therapy CA but not FA nor IGH-GR was significant for the CI of relapse: 33% vs. 15%, p = 0.06. Of the post-transplant follow-up on the CI of relapse, only the 3-mo evaluation was prognostically significant (Table). Although the current findings require further study for confirmation, the data suggests a potential role of IGH-GR tests in monitoring treatment responses in patients with MM. Additional primers such as the ones used in the BIOMED-2 may increase the sensitivity of test. Cumulative Index of Relapse Pre-therapy 3-mo post-transplant 6-mo post-transplant 12-mo post-transplant CA + vs. - 33% vs. 15% P=0.06 43% vs. 18% P = 0.02 50% vs. 23% P = 0.03 33% vs. 13% P = 0.7 FA + vs. - 17% vs. 17% P = 0.52 33% vs. 16% P = 0.02 40% vs. 19% P = 0.67 25% vs. 15% P = 0.16 IGH-GR + vs. - 28% vs. 9% P = 0.57 30% vs. 19% P = 0.001 29% vs. 17% P = 0.3 25% vs. 19% P = 0.37 Disclosures Myint: Seattle Genetics, Inc.: Research Funding.

A rapidly evolving region in the immunoglobulin heavy chain loci of rat and mouse: postulated role of (dC-dA)n · (dG-dT)n sequences

Gene ◽  
1988 ◽  
Vol 68 (1) ◽  
pp. 93-100 ◽  
Author(s):  
Lars Hellman ◽  
Marie-Louise Steen ◽  
Mats Sundvall ◽  
Ulf Pettersson
Keyword(s):  
Heavy Chain ◽  
Immunoglobulin Heavy Chain

scholarly journals Cux/CDP Homeoprotein Is a Component of NF-μNR and Represses the Immunoglobulin Heavy Chain Intronic Enhancer by Antagonizing the Bright Transcription Activator

1999 ◽  
Vol 19 (1) ◽  
pp. 284-295 ◽  
Author(s):  
Zhiyong Wang ◽  
Adrian Goldstein ◽  
Rui-Ting Zong ◽  
Danjun Lin ◽  
Ellis J. Neufeld ◽  
...  
Keyword(s):  
B Cells ◽  
Heavy Chain ◽  
Nuclear Matrix ◽  
Binding Sites ◽  
Immunoglobulin Heavy Chain ◽  
Negative Regulator ◽  
Homeodomain Protein ◽  
Transcription Activator ◽  
Expression Library ◽  
Intronic Enhancer

ABSTRACT Nuclear matrix attachment regions (MARs) flanking the immunoglobulin heavy chain intronic enhancer (Eμ) are the targets of the negative regulator, NF-μNR, found in non-B and early pre-B cells. Expression library screening with NF-μNR binding sites yielded a cDNA clone encoding an alternatively spliced form of the Cux/CDP homeodomain protein. Cux/CDP fulfills criteria required for NF-μNR identity. It is expressed in non-B and early pre-B cells but not mature B cells. It binds to NF-μNR binding sites within Eμ with appropriate differential affinities. Antiserum specific for Cux/CDP recognizes a polypeptide of the predicted size in affinity-purified NF-μNR preparations and binds NF-μNR complexed with DNA. Cotransfection with Cux/CDP represses the activity of Eμ via the MAR sequences in both B and non-B cells. Cux/CDP antagonizes the effects of the Bright transcription activator at both the DNA binding and functional levels. We propose that Cux/CDP regulates cell-type-restricted, differentiation stage-specific Eμ enhancer activity by interfering with the function of nuclear matrix-bound transcription activators.

scholarly journals Evidence for Physical Interaction between the Immunoglobulin Heavy Chain Variable Region and the 3′ Regulatory Region

2007 ◽  
Vol 282 (48) ◽  
pp. 35169-35178 ◽  
Author(s):  
Zhongliang Ju ◽  
Sabrina A. Volpi ◽  
Rabih Hassan ◽  
Nancy Martinez ◽  
Sandra L. Giannini ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Regulatory Region ◽  
Variable Region ◽  
Immunoglobulin Heavy Chain ◽  
Physical Interaction ◽  
Heavy Chain Variable Region

scholarly journals Physiological role of the 3′IgH CBEs super-anchor in antibody class switching

2021 ◽  
Vol 118 (3) ◽  
pp. e2024392118 ◽  
Author(s):  
Xuefei Zhang ◽  
Hye Suk Yoon ◽  
Aimee M. Chapdelaine-Williams ◽  
Nia Kyritsis ◽  
Frederick W. Alt
Keyword(s):  
Regulatory Region ◽  
Physiological Role ◽  
Double Strand Breaks ◽  
Ctcf Binding ◽  
Chromatin Loop ◽  
Strand Breaks ◽  
Class Switch ◽  
Germline Transcription ◽  
Antibody Class

IgH class switch recombination (CSR) replaces Cμ constant region (CH) exons with one of six downstream CHs by joining transcription-targeted double-strand breaks (DSBs) in the Cμ switch (S) region to DSBs in a downstream S region. Chromatin loop extrusion underlies fundamental CSR mechanisms including 3′IgH regulatory region (3′IgHRR)-mediated S region transcription, CSR center formation, and deletional CSR joining. There are 10 consecutive CTCF-binding elements (CBEs) downstream of the 3′IgHRR, termed the “3′IgH CBEs.” Prior studies showed that deletion of eight 3′IgH CBEs did not detectably affect CSR. Here, we report that deletion of all 3′IgH CBEs impacts, to varying degrees, germline transcription and CSR of upstream S regions, except that of Sγ1. Moreover, deletion of all 3′IgH CBEs rendered the 6-kb region just downstream highly transcribed and caused sequences within to be aligned with Sμ, broken, and joined to form aberrant CSR rearrangements. These findings implicate the 3′IgH CBEs as critical insulators for focusing loop extrusion-mediated 3′IgHRR transcriptional and CSR activities on upstream CH locus targets.

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