Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Immunol. Nov 27, 2015; 5(3): 99-112
Published online Nov 27, 2015. doi: 10.5411/wji.v5.i3.99
RNA polymerases in plasma cells trav-ELL2 the beat of a different drum
Sage M Smith, Nolan T Carew, Christine Milcarek
Sage M Smith, Nolan T Carew, Christine Milcarek, Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States
Author contributions: Smith SM and Carew NT contributed equally to this work; Smith SM and Carew NT reviewed literature and wrote text; Milcarek C suggested the theme to be reviewed, reviewed literature, wrote text, and served as principal investigator for primary data.
Supported by The National Science Foundation grant MCB-0842725; National Institutes of Health shared resources Grant No. P30CA047904 to the University of Pittsburgh Cancer Institute; and internal funding from the School of Medicine and Department of Immunology.
Conflict-of-interest statement: The above-mentioned authors hereby declare to have no conflicting interests, including but not limited to commercial, personal, political, intellectual, or religious, related to the work submitted.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Christine Milcarek, PhD, Professor of Immunology, Department of Immunology, School of Medicine, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15213, United States. milcarek@pitt.edu
Telephone: +1-412-6489098 Fax: +1-412-3838096
Received: June 26, 2015
Peer-review started: June 27, 2015
First decision: July 28, 2015
Revised: October 23, 2015
Accepted: November 13, 2015
Article in press: November 17, 2015
Published online: November 27, 2015
Processing time: 153 Days and 20 Hours
Abstract

There is a major transformation in gene expression between mature B cells (including follicular, marginal zone, and germinal center cells) and antibody secreting cells (ASCs), i.e., ASCs, (including plasma blasts, splenic plasma cells, and long-lived bone marrow plasma cells). This significant change-over occurs to accommodate the massive amount of secretory-specific immunoglobulin that ASCs make and the export processes itself. It is well known that there is an up-regulation of a small number of ASC-specific transcription factors Prdm1 (B-lymphocyte-induced maturation protein 1), interferon regulatory factor 4, and Xbp1, and the reciprocal down-regulation of Pax5, Bcl6 and Bach2, which maintain the B cell program. Less well appreciated are the major alterations in transcription elongation and RNA processing occurring between B cells and ASCs. The three ELL family members ELL1, 2 and 3 have different protein sequences and potentially distinct cellular roles in transcription elongation. ELL1 is involved in DNA repair and small RNAs while ELL3 was previously described as either testis or stem-cell specific. After B cell stimulation to ASCs, ELL3 levels fall precipitously while ELL1 falls off slightly. ELL2 is induced at least 10-fold in ASCs relative to B cells. All of these changes cause the RNA Polymerase II in ASCs to acquire different properties, leading to differences in RNA processing and histone modifications.

Keywords: Interferon regulatory factor 4; Antibody secreting cells; B cell differentiation; ELL2; Secretory-specific antibody; B-lymphocyte-induced maturation protein 1; OCA-B; Super elongation complex; Xbp-1; Mammalian target of rapamycin

Core tip: B cell differentiation to antibody secreting cells is a highly regulated, complex process facilitated by factors such as interferon regulatory factor 4, Blimp-1, OCA-B, Xbp1, and mammalian target of rapamycin. This results in a switch in immunoglobulin mRNA processing from the membrane-bound to the secretory-specific form, occurring when ELL2 releases RNAP-II pausing during transcription elongation and causes exon skipping and proximal poly(A) site choice.