Document Detail


Dynamic changes in binding of immunoglobulin heavy chain 3' regulatory region to protein factors during class switching.
MedLine Citation:
PMID:  21685395     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The 3' regulatory region (3' RR) of the Igh locus works at long distances on variable region (V(H)) and switch region (I) region promoters to initiate germ line (non-coding) transcription (GT) and promote class switch recombination (CSR). The 3' RR contains multiple elements, including enhancers (hs3a, hs1.2, hs3b, and hs4) and a proposed insulator region containing CTCF (CCCTC-binding factor) binding sites, i.e. hs5/6/7 and the downstream region ("38"). Notably, deletion of each individual enhancer (hs3a-hs4) has no significant phenotypic consequence, suggesting that the 3' RR has considerable structural flexibility in its function. To better understand how the 3' RR functions, we identified transcription factor binding sites and used chromatin immunoprecipitation (ChIP) assays to monitor their occupancy in splenic B cells that initiate GT and undergo CSR (LPS±IL4), are deficient in GT and CSR (p50(-/-)), or do not undergo CSR despite efficient GT (anti-IgM+IL4). Like 3' RR enhancers, hs5-7 and the 38 region were observed to contain multiple Pax5 binding sites (in addition to multiple CTCF sites). We found that the Pax5 binding profile to the 3' RR dynamically changed during CSR independent of the specific isotype to which switching was induced, and binding focused on hs1.2, hs4, and hs7. CTCF-associated and CTCF-independent cohesin interactions were also identified. Our observations are consistent with a scaffold model in which a platform of active protein complexes capable of facilitating GT and CSR can be formed by varying constellations of 3' RR elements.
Authors:
Sanjukta Chatterjee; Zhongliang Ju; Rabih Hassan; Sabrina A Volpi; Alexander V Emelyanov; Barbara K Birshtein
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-06-17
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-15     Completed Date:  2011-10-19     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  29303-12     Citation Subset:  IM    
Affiliation:
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
B-Cell-Specific Activator Protein / genetics,  metabolism
B-Lymphocytes / cytology,  metabolism*
Immunoglobulin Class Switching / physiology*
Immunoglobulin Heavy Chains / genetics,  immunology,  metabolism*
Mice
Mice, Knockout
Models, Biological*
Repressor Proteins / genetics,  metabolism
Response Elements / physiology*
Spleen / cytology,  metabolism
Grant Support
ID/Acronym/Agency:
AI13509/AI/NIAID NIH HHS; P30 CA13330/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/B-Cell-Specific Activator Protein; 0/CCCTC-binding factor; 0/Immunoglobulin Heavy Chains; 0/Pax5 protein, mouse; 0/Repressor Proteins
Comments/Corrections

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