The mouse IgH 3′‐enhancer

Dariavach, Piona; Williams, Gareth T.; Campbell, Kathy; Pettersson, Sven; Neuberger, Michael S.

doi:10.1002/eji.1830210625

Cited by 135 publications

(104 citation statements)

References 23 publications

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“…The discovery of an enhancer (hs1,2) downstream of the rodent IgH constant region genes was the result of a search for regulatory sequences that could explain IgH gene expression in E -deficient, Ig-secreting cells (32)(33)(34). Chromosome translocations that juxtaposed the oncogene c-myc with the 3Ј end of the Igh locus, resulting in a promoter shift and deregulated c-myc expression, also compelled this search (35,36).…”

Section: Discussionmentioning

confidence: 99%

Transcription of a Productively Rearranged Ig VDJCα Does Not Require the Presence of HS4 in the Igh 3′ Regulatory Region

Zhang

Alaie-Petrillo

Kon

et al. 2007

The Journal of Immunology

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V gene assembly, class switch recombination, and somatic hypermutation are gene-modifying processes essential to the development of an effective Ab response. If inappropriately applied, however, these processes can mediate genetic changes that lead to disease (e.g., lymphoma). A series of control elements within the Ig H chain (Igh) locus has been implicated in regulating these processes as well as in regulating IgH gene transcription. These include the intronic enhancer (Eμ) and several elements at the 3′ end of the locus (hs1,2, hs3a, hs3b, and hs4) known collectively as the 3′ regulatory region. Although it is clear that the Eμ plays a unique role in V gene assembly, it has not been established whether there are unique functions for each element within the 3′ regulatory region. In earlier studies in mice and in mouse cell lines, pairwise deletion of hs3b and hs4 had a dramatic effect on both class switch recombination and IgH gene transcription; deletion of an element almost identical with hs3b (hs3a), however, yielded no discernible phenotype. To test the resulting hypothesis that hs4 is uniquely required for these processes, we induced the deletion of hs4 within a bacterial artificial chromosome transgene designed to closely approximate the 3′ end of the natural Igh locus. When introduced into an Ig-secreting cell line, an Igα transcription unit within the bacterial artificial chromosome was expressed efficiently and the subsequent deletion of hs4 only moderately affected Igα expression. Thus, hs4 does not play a uniquely essential role in the transcription of a productively rearranged Ig VDJCα transcription unit.

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Section: Discussionmentioning

confidence: 99%

Transcription of a Productively Rearranged Ig VDJCα Does Not Require the Presence of HS4 in the Igh 3′ Regulatory Region

Zhang

Alaie-Petrillo

Kon

et al. 2007

The Journal of Immunology

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“…For example, the IgA + B cell with the Ighm/c-myc exchange may already have completed plasmacytic di erentiation, while the IgM + B cell with the Igha/cmyc exchange may still remain at the development stage of a mature lymphocyte. Ongoing clonal diversi®cation generating a continuum of aberrant, di erentiating B cells harboring the t(12;15) at various stages of`remodeling' may thus characterize plasmacytoma development in BALB/c mice that are located 3' of Ca (Pettersson et al, 1990;Dariavach et al, 1991;Matthias and Baltimore, 1993;Madisen and Groudine, 1994;Michaelson et al, 1995). However, 3'-c-myc enhancers have not been identi®ed thus far, and the two candidate enhancer elements that were recently found in a molecular analysis of the 30 kbp downstream region of the human c-myc gene (Mautner et al, 1995) have been shown in subsequent studies to be insu cient to upregulate c-myc expression in vivo (Mautner et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Deletional remodeling of c-myc-deregulating chromosomal translocations

1997

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Evidence is presented for the existence of a novel remodeling-by-deletion mechanism that alters the ®ne structure of c-myc-deregulating chromosomal translocations in t(12;15)-positive BALB/c plasmacytomas. DNA sequence analysis of the t(12;15) in ®ve primary tumors revealed the co-existence of precursor cells harboring genetic recombinations between the immunoglobulin heavy-chain m locus (Ighm) and c-myc with clonally related progenitors containing rearrangements between the immunoglobulin heavy-chain a locus (Igha) and cmyc. Clonal relatedness was based upon unique junction fragments between the switch region of Ighm and c-myc. Sm/c-myc junctions are thus useful clonotypic markers for monitoring the conversion of Ighm/c-myc-positive tumor precursor clones into Igha/c-myc-positive plasmacytomas. Aberrant isotype switch recombination appears to be the most likely mechanism e ecting this conversion event (other possibilities are discussed) which may help to explain the preferred usage of the Igha locus in recombinations with c-myc in t(12;15)-positive plasma cell tumors in BALB/c mice.

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“…Furthermore, the same general region is implicated as an origin of Igh DNA replication in MEL, as inferred from the work of Brown et al (4). The ϳ40-kb region immediately downstream of C␣ that spans the 3Ј Igh regulatory region, as mentioned in the introduction, has only recently been fully described (8,21,24,25,27,29,31). In order to clone sequences downstream of the regulatory region, we screened a 129-OLA phage library (Materials and Methods) with probe 0.7 Hc/E from the extreme 3Ј end of the 23-kb EcoRI fragment (Fig.…”

Section: Isolation Of Sequences Downstream Of the Igh 3 Regulatory Rementioning

confidence: 84%

“…We and others have described a complex 3Ј regulatory region spanning 40 kb downstream of C␣. Four B-cell-specific enhancers, each of which is associated with DNase I hypersensitivity, have been identified in the 3Ј regulatory region (8,21,24,25,27,29,31), as shown in Fig. 1.…”

mentioning

confidence: 99%

Regulation of the Replication of the Murine Immunoglobulin Heavy Chain Gene Locus: Evaluation of the Role of the 3′ Regulatory Region

Michaelson

Ermakova

Birshtein

et al. 1997

Molecular and Cellular Biology

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DNA replication in mammalian cells is a precisely controlled physical and temporal process, likely involving cis-acting elements that control the region(s) from which replication initiates. In B cells, previous studies showed replication timing to be early throughout the immunoglobulin heavy chain (Igh) locus. The implication from replication timing studies in the B-cell line MPC11 was that early replication of the Igh locus was regulated by sequences downstream of the C␣ gene. A potential candidate for these replication control sequences was the 3 regulatory region of the Igh locus. Our results demonstrate, however, that the Igh locus maintains early replication in a B-cell line in which the 3 regulatory region has been deleted from one allele, thus indicating that replication timing of the locus is independent of this region. The faithful duplication of the mammalian genome by DNA replication occurs in a physically and temporally ordered fashion during each round of S phase. In contrast to Escherichia coli, in which bidirectional DNA replication of a circular chromosome usually initiates at a single defined origin of replication (10, 26), the significantly larger genome in higher organisms requires DNA synthesis to initiate at multiple origins. Questions regarding where replication initiates and what controls replication initiation are fundamental in understanding the ordered program of DNA replication.DNA replication in eukaryotes does not initiate from all origins simultaneously; rather, replication origins fire in a programmed manner at fixed intervals during S phase. A relationship between transcriptional activity and early timing of replication has been observed, suggestive of potential coregulation of the two processes. Housekeeping genes, accordingly, replicate relatively early in S phase in most cell types (34). Tissuespecific genes also generally replicate early in S phase in cell types in which they are expressed; however, they often replicate late when they are not transcribed. The ␤-globin locus, for example, is early replicating in murine erythroleukemia cells (MEL) and late replicating in other cell types, such as lymphocytes (13, 18). Significantly, the same origin, located between the ␦-and ␤-globin genes, is utilized in both erythroleukemia cells and lymphocytes (references 1 and 20 and references therein).For the mouse immunoglobulin heavy chain (Igh) locus, the temporal order of Igh gene replication has been assessed by measuring the relative concentrations of EcoRI restriction fragment segments in 5-bromouracil-labeled DNA (BU-DNA) during various intervals of S phase (4). The murine Igh locus is comprised of variable region genes, including V (variable), D (diversity), and J (joining) segments, and constant region genes. (The Igh genes are arranged on chromosome 12 as follows: telomere-V-D-J-C H -centromere. The terms "downstream" and "3Ј" are used in this article with reference to the transcriptional orientation of the Igh genes in B cells.) In non-B cells, such as MEL, the 3Ј-most constan...

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The mouse IgH 3′‐enhancer

Cited by 135 publications

References 23 publications

Transcription of a Productively Rearranged Ig VDJCα Does Not Require the Presence of HS4 in the Igh 3′ Regulatory Region

Transcription of a Productively Rearranged Ig VDJCα Does Not Require the Presence of HS4 in the Igh 3′ Regulatory Region

Deletional remodeling of c-myc-deregulating chromosomal translocations

Regulation of the Replication of the Murine Immunoglobulin Heavy Chain Gene Locus: Evaluation of the Role of the 3′ Regulatory Region

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