Abstract
The Igh locus undergoes an amazing array of DNA rearrangements and modifications during B cell development. During early stages, the variable region gene is constructed from constituent variable (V), diversity (D), and joining (J) segments (VDJ joining). B cells that successfully express an antibody can be activated, leading to somatic hypermutation (SHM) focused on the variable region, and class switch recombination (CSR), which substitutes downstream constant region genes for the originally used Cμ constant region gene. Many investigators, ourselves included, have sought to understand how these processes specifically target the Igh locus and avoid other loci and potential deleterious consequences of malignant transformation. Our laboratory has concentrated on a complex regulatory region (RR) that is located downstream of Ca, the most 3' of the Igh constant region genes. The ∼40 kb 3' RR, which is predicted to serve as a downstream major regulator of the Igh locus, contains two distinct segments: an ∼28 kb region comprising four enhancers, and an adjacent ∼12 kb region containing multiple CTCF and Pax5 binding sites. Analysis of targeted mutations in mice by a number of investigators has concluded that the entire 3' RR enhancer region is essential for SHM and CSR (but not for VDJ joining) and for high levels of expression of multiple isotypes. The CTCF/Pax5 binding region is a candidate for influencing VDJ joining early in B cell development and serving as a potential insulator of the Igh locus. Components of the 3' RR are subject to a variety of epigenetic changes during B cell development, i.e., DNAse I hypersensitivity, histone modifications, and DNA methylation, in association with transcription factor binding. I propose that these changes provide a foundation by which regulatory elements in modules of the 3' RR function by interacting with each other and with target sequences of the Igh locus.
| Original language | English (US) |
|---|---|
| Article number | Article 163 |
| Journal | Frontiers in Immunology |
| Volume | 5 |
| Issue number | APR |
| DOIs | |
| State | Published - 2014 |
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Keywords
- Class switch recombination
- CTCF
- Enhancers
- Immunoglobulin heavy chain gene locus
- Insulators
- Pax5
- Somatic hypermutation
ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
Cite this
Epigenetic regulation of individual modules of the immunoglobulin heavy chain locus 3' regulatory region. / Birshtein, Barbara K.
In: Frontiers in Immunology, Vol. 5, No. APR, Article 163, 2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Epigenetic regulation of individual modules of the immunoglobulin heavy chain locus 3' regulatory region
AU - Birshtein, Barbara K.
PY - 2014
Y1 - 2014
N2 - The Igh locus undergoes an amazing array of DNA rearrangements and modifications during B cell development. During early stages, the variable region gene is constructed from constituent variable (V), diversity (D), and joining (J) segments (VDJ joining). B cells that successfully express an antibody can be activated, leading to somatic hypermutation (SHM) focused on the variable region, and class switch recombination (CSR), which substitutes downstream constant region genes for the originally used Cμ constant region gene. Many investigators, ourselves included, have sought to understand how these processes specifically target the Igh locus and avoid other loci and potential deleterious consequences of malignant transformation. Our laboratory has concentrated on a complex regulatory region (RR) that is located downstream of Ca, the most 3' of the Igh constant region genes. The ∼40 kb 3' RR, which is predicted to serve as a downstream major regulator of the Igh locus, contains two distinct segments: an ∼28 kb region comprising four enhancers, and an adjacent ∼12 kb region containing multiple CTCF and Pax5 binding sites. Analysis of targeted mutations in mice by a number of investigators has concluded that the entire 3' RR enhancer region is essential for SHM and CSR (but not for VDJ joining) and for high levels of expression of multiple isotypes. The CTCF/Pax5 binding region is a candidate for influencing VDJ joining early in B cell development and serving as a potential insulator of the Igh locus. Components of the 3' RR are subject to a variety of epigenetic changes during B cell development, i.e., DNAse I hypersensitivity, histone modifications, and DNA methylation, in association with transcription factor binding. I propose that these changes provide a foundation by which regulatory elements in modules of the 3' RR function by interacting with each other and with target sequences of the Igh locus.
AB - The Igh locus undergoes an amazing array of DNA rearrangements and modifications during B cell development. During early stages, the variable region gene is constructed from constituent variable (V), diversity (D), and joining (J) segments (VDJ joining). B cells that successfully express an antibody can be activated, leading to somatic hypermutation (SHM) focused on the variable region, and class switch recombination (CSR), which substitutes downstream constant region genes for the originally used Cμ constant region gene. Many investigators, ourselves included, have sought to understand how these processes specifically target the Igh locus and avoid other loci and potential deleterious consequences of malignant transformation. Our laboratory has concentrated on a complex regulatory region (RR) that is located downstream of Ca, the most 3' of the Igh constant region genes. The ∼40 kb 3' RR, which is predicted to serve as a downstream major regulator of the Igh locus, contains two distinct segments: an ∼28 kb region comprising four enhancers, and an adjacent ∼12 kb region containing multiple CTCF and Pax5 binding sites. Analysis of targeted mutations in mice by a number of investigators has concluded that the entire 3' RR enhancer region is essential for SHM and CSR (but not for VDJ joining) and for high levels of expression of multiple isotypes. The CTCF/Pax5 binding region is a candidate for influencing VDJ joining early in B cell development and serving as a potential insulator of the Igh locus. Components of the 3' RR are subject to a variety of epigenetic changes during B cell development, i.e., DNAse I hypersensitivity, histone modifications, and DNA methylation, in association with transcription factor binding. I propose that these changes provide a foundation by which regulatory elements in modules of the 3' RR function by interacting with each other and with target sequences of the Igh locus.
KW - Class switch recombination
KW - CTCF
KW - Enhancers
KW - Immunoglobulin heavy chain gene locus
KW - Insulators
KW - Pax5
KW - Somatic hypermutation
UR - http://www.scopus.com/inward/record.url?scp=84900873309&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84900873309&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2014.00163
DO - 10.3389/fimmu.2014.00163
M3 - Article
AN - SCOPUS:84900873309
VL - 5
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
IS - APR
M1 - Article 163
ER -