Poster abstracts

Poster number 84 submitted by Zhitao Liang

Alternative RNA splicing accompanies loss of ELL2 in mouse B cells

Zhitao Liang (Immunology, University of Pittsburgh), Sage Smith (Immunology, University of Pittsburgh), Nolan Carew (Immunology, University of Pittsburgh), Ashley Dunham (Immunology, University of Pittsburgh), Christine Milcarek (Immunology, University of Pittsburgh)

Abstract:
The ELL2 transcription elongation factor is induced by Lipopolysaccharide treatment of B cells and is crucial for the subsequent processing of secretory-specific immunoglobulin heavy chain mRNA (1). A conditional knockout of ELL2 in mouse B cells shows reduced amounts of: IgH secretory mRNA, serum Ig, the secretory protein apparatus, as well as antibody secreting and long-lived plasma cells (2). ELL2 thus drives Ig mRNA production and the unfolded protein response leading to Ig secretion. Human mutants in ELL2 give rise to myeloma (a tumor of long lived plasma cells), reduced serum Ig, and increased susceptibility to infectious diseases.

To investigate a potential role for ELL2 in myeloma formation, we have investigated alternative splicing in B cell development. Using mRNA seq and ChIP-seq we have identified several alternatively spliced ELL2 target genes in the ELL2 conditional knockout B cells. One interesting alternatively spliced gene is XafI, the full length version of which normally interacts with XIAP to modulate cell growth. In many types of tumor cells exon 4 of XafI is frequently deleted by splicing, as it is in ELL2 conditional knockout cells. We are determining if the splicing variations in XafI contribute to changes in the growth properties of the ELL2 knockout cells and possibly to myeloma. Modifications of the RNAP-II elongation by ELL2 thus may have far-reaching consequences in the immune system.

References:
1. Martincic, K., S. A. Alkan, A. Cheatle, L. Borghesi, and C. Milcarek. 2009. Transcription elongation factor ELL2 directs immunoglobulin secretion in plasma cells by stimulating altered RNA processing. Nat Immunol 10:1102-1109.
2. Park, K. S., I. Bayles, A. Szlachta-McGinn, J. Paul, J. Boiko, P. Santos, J. Liu, Z. Wang, L. Borghesi, and C. Milcarek. 2014. Transcription elongation factor ELL2 drives immunoglobulin secretory specific mRNA production and the unfolded protein response. J. Immunol. 193:4663-4674.

Keywords: Splicing, Transcription, B cell development