Mediator: Keep me in the loop
In the IgH locus, specific genes encodes the different antibodies classes. Eμ and 3'E enhancer elements contribute to optimal regulation of the locus. B lymphocytes only express IgM antibodies. During infection, infection, B cells undergo class switch recombination (CSR), during which they re-arrange the IgH locus through DNA recombination. This results in the change of expressed antibody class (e.g. IgG1). DNA recombination requires the formation of long-range DNA loops between enhancers and promoters. It depends on the transcriptional activation of the locus. The Mediator complex facilitates dynamic 3D-structural contacts within the IgH locus and its transcriptional activation, thereby promoting efficient CSR. The absence of Med1 subunit contribute to defective isotype switching.
Feb. 22, 2016
Antibodies are essential to defend our organism against pathogens. In a new study published on 22th February 2016 in the Journal of Experimental Medicine the team of Bernardo Reina San-Martin at IGBMC revealed a new mechanism driving to antibody diversification. They have shown that the Mediator complex regulates the transcriptional activation of the immunoglobulin heavy chain (IgH) locus by facilitating long-range contacts between the IgH enhancers and promoters. This work provides novel insight into the mechanisms regulating the 3D-changes of the IgH locus, which are required for the efficient generation of adapted antibody responses.
Diversify and adapt
Our immune system is constantly challenged by thousands of pathogens. To fight infections, B lymphocytes secrete antibodies, molecules capable of recognizing a large array of antigens. Despite the large repertoire of antibodies present in the body that can respond to an infection, these are not necessarily capable of efficiently neutralizing pathogens. Hence, upon infection, two mechanisms optimize antibody function through DNA alteration events that take place at antibody-coding genes (immunoglobulin loci). While somatic hypermutation (SHM) mutates the regions encoding the antigen-binding site to generate highly specific antibodies, class switch recombination (CSR) allows B cells to change the type of antibody they produce (from IgM to IgA, IgG or IgE) to provide novel effector functions. Together, SHM and CSR establish highly specific, pathogen-adapted and long-lasting protective antibody responses.
Long-range loops, transcriptional activation and DNA recombination
Although all the different antibody classes are encoded by specific genes in the immunoglobulin heavy chain (IgH) locus, mature B cells initially express IgM antibodies. Upon antigen recognition, B cells re-arrange the IgH locus to express a novel antibody class (IgG, IgE or IgA) through a DNA recombination event that depends on the formation long-range DNA loops between enhancers and promoters and the concomitant transcriptional activation of the locus. Mechanistically, how these long-range interactions are established and/or maintained during CSR is totally unknown.
Mediator links transcription and DNA loops during class switch recombination
To get insight into this mechanism, the team of Bernardo Reina-San-Martin focused on the Mediator complex, a central integrator of transcription that has been suggested to promote DNA looping between regulatory regions and gene promoters. They show that the Mediator complex facilitates dynamic 3D-structural changes of the IgH locus and its transcriptional activation, thereby promoting efficient long-range DNA recombination.
These results reveal for the first time the role of the Mediator complex in the establishment and/or maintenance of long-range interactions during CSR and they contribute to delineate the mechanisms that support the robust generation of new antibody classes to establish highly adapted humoral responses.