Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression

• Published in: Molecular immunology Vol. 77; pp. 97 - 102
• Main Authors: Jones, Bart G., Penkert, Rhiannon R., Xu, Beisi, Fan, Yiping, Neale, Geoff, Gearhart, Patricia J., Hurwitz, Julia L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2016
• Subjects: Animals; Antibody Formation - genetics; Antibody Formation - immunology; B-Lymphocytes - immunology; Chromatin Immunoprecipitation; Class switch recombination; Enhancers; Estrogen response elements; Female; Gene Expression Regulation - immunology; Humans; Immunoglobulin heavy chain locus; Immunoglobulin Heavy Chains - immunology; Immunoglobulin Switch Region - immunology; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Polymerase Chain Reaction; Receptors, Estrogen - immunology; Receptors, Estrogen - metabolism; Response Elements - immunology; Switch site; CSR; C; D; Immunoglobulin heavy chain locus; J; hs; ER; Switch site; Enhancers; S; Class switch recombination; Estrogen response elements; V; ERE; AID
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2016.07.015

•Hotspots for estrogen receptor response elements exist in Sμ, Sε, and Sα regions within murine and human immunoglobulin heavy chain loci.•ERE are rare within all Sγ regions in immunoglobulin heavy chain loci of mice and humans.•A ChIP-seq experiment using purified female mouse B cells stimulated for 1day with LPS revealed binding of estrogen receptor α to the Sμ region.•Additional peaks of binding were in the intronic enhancer Eμ and the 3′regulatory region (3′RR), particularly hs1,2 and hs4 sites.•Results suggest that there may be a direct influence of estrogen and other hormones or vitamins on antibody expression patterns. Females and males differ in antibody isotype expression patterns and in immune responses to foreign- and self-antigens. For example, systemic lupus erythematosus is a condition that associates with the production of isotype-skewed anti-self antibodies, and exhibits a 9:1 female:male disease ratio. To explain differences between B cell responses in males and females, we sought to identify direct interactions of the estrogen receptor (ER) with the immunoglobulin heavy chain locus. This effort was encouraged by our previous identification of estrogen response elements (ERE) in heavy chain switch (S) regions. We conducted a full-genome chromatin immunoprecipitation analysis (ChIP-seq) using DNA from LPS-activated B cells and an ERα-specific antibody. Results revealed ER binding to a wide region of DNA, spanning sequences from the JH cluster to Cδ, with peaks in Eμ and Sμ sites. Additional peaks of ERα binding were coincident with hs1,2 and hs4 sites in the 3′ regulatory region (3′RR) of the heavy chain locus. This first demonstration of direct binding of ER to key regulatory elements in the immunoglobulin locus supports our hypothesis that estrogen and other nuclear hormone receptors and ligands may directly influence antibody expression and class switch recombination (CSR). Our hypothesis encourages the conduct of new experiments to evaluate the consequences of ER binding. A better understanding of ER:DNA interactions in the immunoglobulin heavy chain locus, and respective mechanisms, may ultimately translate to better control of antibody expression, better protection against pathogens, and prevention of pathologies caused by auto-immune disease.