# mRNA alternative polyadenylation in B cell development

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $793,986

## Abstract

Project summary:
The vast majority of mammalian genes produce alternatively processed mRNAs through
alternative splicing and alternative polyadenylation (APA). Different mRNA isoforms produced
from the same gene can encode distinct proteins and/or they may be differentially regulated.
Recent studies have revealed essential roles of mRNA alternative processing in many biological
processes and mis-regulation of alternative splicing and APA has been causally linked to a wide
range of diseases, including cancer and neurodegenerative diseases. However, the mechanism
and functions of alternative mRNA processing remain poorly understood.Antibody secretion by B
cells is a major component of our immune response and mis-regulated antibody response
underlies many auto-immune diseases. B cell activation and differentiation require a sophisticated
gene regulation cascade. Previous works, including ours, have provided insights into the
transcriptional regulation mechanisms governing this process. However, it is clear that post-
transcriptional gene regulation, such as alternative splicing and APA, also play an important role.
In 1980, several landmark studies reported the first example of alternative RNA processing: the
Immunoglobulin M (IgM) heavy chain gene (IghM) produces two APA isoforms, which encode a
membrane-bound and a secreted IgM respectively. Additionally the IghM APA is developmentally
regulated. Subsequent studies, however, have failed to provide a consistent mechanistic model
for this APA switch. Furthermore, it remains unknown how widespread the APA regulation
network is and what the functional impact of APA regulation is during B cell activation and
differentiation. In our preliminary studies, we provided evidence that transcription factors, core
mRNA 3’ processing factors, and RNA-binding proteins regulate IghM APA. In addition, we
discovered that B cell activation leads to a significantly change in the APA patterns of ~900 genes,
including those encoding key cell fate regulators and signaling proteins. Based on these
preliminary results, we hypothesize that the APA of IghM and a large gene network are regulated
at multiple levels and that APA regulation plays an important role in B cell functions. To test these
hypotheses, we have designed the following specific aims: 1) Identify regulators of B cell
activation-induced IghM APA switch using a biochemical and genetic approach; 2) Systematically
characterize the mechanisms of B cell activation-induced IghM APA switch; 3) Determine the role
of APA regulation in B cell activation and differentiation. Successful completion of the proposed
studies will provide fundamental insights into APA regulation and function. More importantly, our
results will reveal the role of post-transcriptional gene regulation in B cell development and B cell-
mediated immune response, which will pave the way for better strategies for developing vaccines
and treatment for autoimmune diseases.

## Key facts

- **NIH application ID:** 10502155
- **Project number:** 1R01AI170840-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Roger Sciammas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $793,986
- **Award type:** 1
- **Project period:** 2022-05-26 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10502155

## Citation

> US National Institutes of Health, RePORTER application 10502155, mRNA alternative polyadenylation in B cell development (1R01AI170840-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10502155. Licensed CC0.

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