Hide and Go Seek: Activation of the Secretory-Specific Poly (A) Site of Igh by Transcription Elongation Factors

Abstract

The regulation of the immunoglobulin heavy chain (Igh) alternative RNA processing has served as a model system for revealing the competition between cis and trans-acting RNA factors influencing splicing and polyadenylation, reviewed in (Peterson 2007) and (Borghesi and Milcarek 2006). This review will explore recent studies on the role of transcription elongation factors in the super elongation complex (SEC) including ELL2 (eleven-nineteen lysine rich leukemia factor) on driving poly(A) site choice. Elongation factors impel high levels of Igh mRNA production and alternative processing at the promoter proximal, secretory-specific poly(A) site (sec) in plasma cells by enhancing RNA polymerase II modifications and downstream events. The sec poly(A) site, essentially hidden in B cells, is found by SEC factors in plasma cells. Most mRNAs have a poly(A) tail and it has been estimated that up to 20% of the human genes may be arranged with a competition of splicing and polyadenylation sites as seen in the Igh (Tian, Pan et al. 2007; Rigo and Martinson 2008). Numerous genes contain multiple poly(A) sites (Tian, Hu et al. 2005); many subject to regulation (Edwalds-Gilbert, Veraldi et al. 1997) and (Lutz and Moreira 2011). Advancing developmental stage is generally correlated with use of promoter distal poly(A) sites (Ji, Lee et al. 2009; Ji and Tian 2009). Yet the opposite situation applies as B-cells terminally differentiate into plasma cells; elongation factors may hold the key to understanding this apparent paradox. Transcriptional pausing and subsequent elongation are emerging as important check points for gene regulation. Phosphorylation of the carboxyl-terminal domain of RNAP-II by initiation and elongation factors directs the correct associations to ultimately drive mature mRNA output. The SEC, composed of nine proteins including pTEFb and ELL (see key), kick starts elongation by facilitating the phosphorylation of both the negative acting factors that have stalled the polymerase and polymerase itself. The mPAF is recruited by the action of the pTEFb through phosphorylation of the serine-2 of the RNA polymerase carboxylterminal domain heptad repeat; mPAF brings along with it the polyadenylation factors. The factors that polyadenylate mRNA are more strongly associated with the polymerase transcription complex on highly active promoters and/ or through up-regulation of the polyadenylation and elongation factors, especially CstF (cleavage stimulatory factor), pTEFb, and ELL2. Polymerases deficient in the appropriate factors may transit the gene, but