scholarly journals A 220-nucleotide deletion of the intronic enhancer reveals an epigenetic hierarchy in immunoglobulin heavy chain locus activation

2009 ◽  
Vol 206 (5) ◽  
pp. 1019-1027 ◽  
Author(s):  
Tirtha Chakraborty ◽  
Thomas Perlot ◽  
Ramesh Subrahmanyam ◽  
Anant Jani ◽  
Peter H. Goff ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Immunoglobulin Heavy Chain ◽  
Specific Gene ◽  
Transcriptional Enhancer ◽  
Developmentally Regulated ◽  
Tissue Specific ◽  
Intronic Enhancer ◽  
Active Locus ◽  
Specific Locus ◽  
H3k9 Dimethylation

A tissue-specific transcriptional enhancer, Eμ, has been implicated in developmentally regulated recombination and transcription of the immunoglobulin heavy chain (IgH) gene locus. We demonstrate that deleting 220 nucleotides that constitute the core Eμ results in partially active locus, characterized by reduced histone acetylation, chromatin remodeling, transcription, and recombination, whereas other hallmarks of tissue-specific locus activation, such as loss of H3K9 dimethylation or gain of H3K4 dimethylation, are less affected. These observations define Eμ-independent and Eμ-dependent phases of locus activation that reveal an unappreciated epigenetic hierarchy in tissue-specific gene expression.

Presence of N regions in the clonotypic DJ rearrangements of the immunoglobulin heavy-chain genes indicates an exquisitely short latency in t(4;11)-positive infant acute lymphoblastic leukemia

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2272-2274 ◽  
Author(s):  
Karin Fasching ◽  
Simon Panzer ◽  
Oskar A. Haas ◽  
Arndt Borkhardt ◽  
Rolf Marschalek ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Heavy Chain ◽  
Lymphoblastic Leukemia ◽  
Latency Period ◽  
Immunoglobulin Heavy Chain ◽  
In Utero ◽  
Cell Precursor ◽  
Developmentally Regulated ◽  
Igh Genes ◽  
Immunoglobulin Heavy Chain Genes

Childhood acute lymphoblastic leukemia (ALL) is frequently initiated in utero at a time of developmentally regulated insertion of N regions into the DJH rearrangements of immunoglobulin heavy-chain (IgH) genes. Here it is shown that N regions are present in the clonotypic DJH rearrangements in 11 of 12 infant ALLs with t(4;11). These data are compared with the 122 previously published DJH sequences and were found to have a pattern similar to that of ALL in children older than 3 years at diagnosis but were unlike that in children younger than 3 years who predominantly lack N regions. These findings, therefore, indicate that t(4;11)-positive infant ALL is initiated later in fetal development than most B-cell precursor ALL from children younger than 3 years and that they have a shorter latency period already in utero.

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.

Minimal membrane and secreted μ poly(A) signals specify developmentally-regulated immunoglobulin heavy chain mRNA ratios without RNA splicing

1994 ◽  
Vol 31 (7) ◽  
pp. 563-566
Author(s):  
Nicolas J. Fasel ◽  
Nicole Deglon ◽  
Carole Beghdadi-Rais ◽  
Ronald Law ◽  
Claude Bron ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Rna Splicing ◽  
Immunoglobulin Heavy Chain ◽  
Developmentally Regulated

scholarly journals The immunoglobulin heavy chain locus contains another B-cell-specific 3' enhancer close to the alpha constant region.

1993 ◽  
Vol 13 (3) ◽  
pp. 1547-1553 ◽  
Author(s):  
P Matthias ◽  
D Baltimore
Keyword(s):  
Transcription Factors ◽  
B Cell ◽  
Heavy Chain ◽  
Variable Region ◽  
Immunoglobulin Heavy Chain ◽  
Immunoglobulin Genes ◽  
Constant Region ◽  
Transcriptional Enhancer ◽  
Additional Control ◽  
Complex Regulation

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.

scholarly journals The V(D)J recombinational and transcriptional activities of the immunoglobulin heavy-chain intronic enhancer can be mediated through distinct protein-binding sites in a transgenic substrate.

1995 ◽  
Vol 15 (6) ◽  
pp. 3217-3226 ◽  
Author(s):  
C Fernex ◽  
M Capone ◽  
P Ferrier
Keyword(s):  
Heavy Chain ◽  
Transcriptional Activation ◽  
Germ Line ◽  
Receptor Gene ◽  
Immunoglobulin Heavy Chain ◽  
Cell Receptor ◽  
Regulatory Sequences ◽  
Intronic Enhancer ◽  
Molecular Events ◽  
Activation Of Transcription

Immunoglobulin and T-cell receptor gene transcriptional enhancers encompass sequences which stimulate V(D)J recombination of associated variable gene segments. To address the question of whether enhancer-mediated transcriptional activation and recombinational activation depend on the same cis-regulatory sequences, we have produced transgenic mice by using recombination substrates containing various mutations in the immunoglobulin heavy-chain intronic enhancer (E mu). Analysis of substrate rearrangements indicated that specific compound elements including E-box transcriptional motifs are crucial for the recombinational activity of E mu in the developing B and T lymphocytes. In most cases, a faithful correlation between the levels of substrate germ line transcription and recombination was observed. However, some of the E mu mutants which were able to activate transcription of the unrearranged substrate were inefficient in stimulating transgene recombination, implying that the latter function depends on molecular events other than the mere activation of transcription and that both activities can be mediated through distinct regulatory sequences. Together, these results support a model in which lymphoid gene enhancers, in addition to providing docking sites for factors that dictate transcriptional accessibility, must have some specific function(s) for activating V(D)J recombination.

Immunoglobulin Heavy Chain (IGH) Gene Rearrangement In Waldenström Macroglobulinemia and Other Monoclonal IgM Disorders

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4139-4139
Author(s):  
Marzia Varettoni ◽  
Silvia Zibellini ◽  
Luca Arcaini ◽  
Ester Orlandi ◽  
Cristiana Pascutto ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Gene Rearrangement ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
International Workshop ◽  
Immunoglobulin Heavy Chain ◽  
Specific Gene ◽  
Limited Information ◽  
Gene Usage ◽  
Igh Gene Rearrangement

Abstract Abstract 4139 Background. The presence of a serum IgM monoclonal component is associated with a spectrum of lymphoid disorders including Waldenström Macroglobulinemia (WM), IgM monoclonal gammopathy of undetermined significance (MGUS) and IgM-related disorders (IgM-RD). Limited information is available on immunoglobulin heavy chain (IGH) gene rearrangement in this setting. Purpose. The aim of this study was to analyze IGHV-D-J rearrangements in a large series of patients (pts) and to compare the gene usage across different monoclonal IgM disorders. Patients and methods. We analyzed 107 pts including 52 WM, 47 IgM MGUS and 8 IgM-RD. Diagnosis was made according to the consensus criteria proposed at the 2nd International Workshop on WM. Mononuclear cells were obtained from bone marrow in all pts. IGHV-D-J rearrangements were amplified and directly sequenced from cDNA using primers specific for each of the leader sequences of HV1-6 subgroups in combination with a joining heavy chain (JH) consensus primer or cμ constant region primer. Sequences were aligned to ImMunoGeneTics sequence directory using the IMGT V-QUEST analysis software. Results. A complete productive monoclonal IGHV-D-J rearrangement was obtained in 84/107 cases (78%). Using a homology cut-off value of 98% to the nearest germline gene, we observed mutated IGHV in 79/84 pts (94%) and unmutated IGHV in 5 (6%). The frequency of IGHV, IGHD and IGHJ gene usage is shown in the table. The most common IGHV subgroup was IGHV3, which was found in 69/84 cases (82%). The individual IGHV genes most frequently used were IGHV3-23 (20/84, 24%) and IGHV3-7 (10/84, 12%). IGHD segments were assignable in 83 out of 84 rearrangements. The most represented IGHD subgroups were IGHD3 (23/83, 28%), IGHD6 (16/83, 19%) and IGHD2 (15/83, 18%). The most common individual IGHD genes were IGHD6-19 (10/83, 12%) and IGHD2-2 (8/83, 10%). The analysis of IGHJ genes showed a preferential usage of IGHJ4 gene (56/84, 67%) and IGHJ4*02 allele (54/84, 64%). The median HCDR3 length was 13 amino acids (range: 5–29). We found an association between IGHV3 and IGHJ4 subgroups (p=0.01), while no association was found between IGHV and IGHD (p=0.8), and between IGHD and IGHJ subgroups (p=0.8). We compared IGH rearrangement features in pts with WM, MGUS and IgM-RD. A complete productive monoclonal IGHV-D-J rearrangement was detected in a higher percentage of WM pts (47/52, 90%) as compared to MGUS (31/47, 66%) and IgM-RD pts (6/8, 75%) (p=0.01). The proportion of mutated IGHV cases was similar in the three groups (p=0.6). Regarding specific gene usage, there was a trend toward a higher usage of IGHV3-23 gene in WM (14/47, 30%) as compared to MGUS (4/31, 13%) (p=0.07). On the contrary, there was no difference in distribution of IGHD subgroups (p=0.13) and IGHJ genes (p=0.5). The median HCDR3 length was similar in WM, MGUS and IgM-RD (p=0.6). We also compared IGHV usage with clinical characteristics of pts. Interestingly, we found that autoimmune manifestations were more frequently observed in pts carrying IGHV4-34 gene (3/4, 75%) as compared to pts using alternative genes (8/80 pts, 10%) (p=0.006). Autoimmune phenomena associated with IGHV4-34 gene were represented by cold agglutinin haemolytic anemia in 2 pts with IgM-RD and 1 with WM. Conclusions: the identification of a monoclonal IGHV-D-J rearrangement seems more feasible in WM as compared to MGUS and IgM-RD. In all three groups, the majority of cases are mutated, confirming the derivation of the clone from a post-germinal center cell. This study shows a preferential usage of VH3 subgroup and in particular of VH3-23 gene, with a trend for a higher usage in WM as compared to other IgM disorders. A higher prevalence of autoimmune manifestations was observed in pts carrying VH4-34 gene. Disclosures: No relevant conflicts of interest to declare.

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