25 January 2016

Novel protein complex generates antibody diversity

Antibody class-switching is crucial for generating certain types of antibodies, such as IgG, that can help to clear infections from the body. To generate these antibodies, B cells initiate a cut-and-paste DNA rearrangement reaction during an immune response that we call class-switch recombination (CSR). These programmed DNA damage events occur at the immunoglobulin heavy chain (IgH) locus and must be carefully controlled to minimize further genomic instability and cancer. Transcription of the IgH locus is an essential feature of the mechanism that targets DNA break formation during CSR. While much has been learned about cis-acting elements that control the expression of the IgH locus, our understanding of how chromatin remodelling and histone post-translational modifications influence the targeting and stability of the IgH locus remain largely unclear.  

In a study led by Linda Starnes in the Daniel group, the authors revealed an unexpected function for a subcomplex of proteins consisting of PTIP and PA1 in promoting transcription of certain types of antibodies through a mechanism independent from their well-known association with the MLL3/MLL4 histone methyltransferase complex. The authors go on to show that this CSR function of the BRCT domain-containing PTIP protein occurs separately from its localization to sites of DNA damage. By performing quantitative interaction proteomics of different PTIP-associated protein complexes, the authors were able to make predictions for how PTIP functions in CSR and then verify them using PA1- and MLL3/MLL4-deficient mouse models. Along with identifying PA1 as a novel antibody class-switching factor, the study shows for the first time a specific function for the PTIP/PA1 subcomplex and opens up further avenues of investigation to study the relationship between histone methylation and transcription during antibody gene diversification. These findings may have important implications for the design of treatments for antibody-driven pathologies such as hypogammaglobulinemia or some autoimmune diseases. 

Title:
A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex 

Authors from CPR:
Linda M. Starnes
Dan Su
Laura Pikkupeura
Brian T. Weinert
Andreas Mund
Rebeca Soria
Irina Pozdnyakova
Martina Kubec Højfeldt
Andrea Vala
Blanca Lopez-Mendez
Guillermo Montoya
Chunaram Choudhary
Jeremy A. Daniel

Link to the article in Genes & Development