Plasma cell gene expression depends on ELL2 (176.15)

Abstract From studies with splenic B cells and cell lines ELL2, a transcription elongation factor, was found to play a vital role in the differentiation of B cells into plasma cells. It is responsible for Igh mRNA being both alternatively processed to the secretory-specific form and increased in abundance, leading to high levels of secreted Ig protein and a robust immune response. To investigate the molecular mechanisms that occur as a result of ELL2 action, we studied histone H3 methylation at K4 and K79 on the Igh in plasma cells by chromatin IP. We found that knocking out ELL2 with siRNA decreases the H3K4 di- and tri-methylation and K79 tri-methylation patterns as well as the association of CstF-64 and pTEFb, a part of the super elongation complex. Recent chromatin IP studies show that ELL2 is associated with RNA polymerase II on essential regulatory plasma cell genes including IRF-4 and blimp-1. Using luciferase transcription assays we show that ELL2 is able to increase transcription from its own and the IRF-4 promoter. Elongation is thus linked to increased mRNA production and the use of a proximal poly(A) site in the IRF-4 gene. ELL2 and ELL1 do not have identical patterns of action. Taken together, these studies define a fundamental role for ELL2 in the transcription elongation machinery and RNA processing in plasma cell differentiation. Studies on the in vivo role of ELL2 in Ig secretion are in progress.