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Principal Investigator: Roger Sciammas
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2023
Award: $776,774
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <19S Gamma Globulin><Alleles><Allelomorphs><Alternate Splicing><Alternative RNA Splicing><Alternative Splicing><Antibodies><Antibody Response><Autoimmune Diseases><B blood cells><B cell><B cells><B-Cell Activation><B-Cell Development><B-Cells><B-Lymphocytes><B-cell><Basal Transcription Factor><Basal transcription factor genes><Binding><Biochemical><Biological Function><Biological Process><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cancers><Cell Body><Cell Function><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Complex><Data><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Development><Disease><Disorder><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><General Transcription Factor Gene><General Transcription Factors><Genes><IgM><Immune response><Immunoglobulin M><Immunological response><Individual><Isoforms><Link><Malignant Neoplasms><Malignant Tumor><Membrane><Messenger RNA><Modeling><Molecular Interaction><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Pattern><Play><Poly A><Poly(rA)><Polyadenylation><Post-Transcriptional Control><Post-Transcriptional Regulation><Process><Protein Isoforms><Proteins><RNA Polyadenylation><RNA Processing><RNA-Binding Proteins><Regulation><Reporter><Reporting><Role><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Subcellular Process><Testing><Transcript><Transcription Activation><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Activation><Transcriptional Control><Transcriptional Regulation><Work><activated B cells><autoimmune condition><autoimmune disorder><autoimmunity disease><cell mediated immune response><clustered regularly interspaced short palindromic repeats screen><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><gene network><genetic approach><genetic strategy><genome scale><genome-wide><genomewide><host response><immune system response><immunoresponse><insight><mRNA><malignancy><membrane structure><neoplasm/cancer><neurodegenerative illness><novel><polyadenylate><post-transcriptional gene regulation><posttranscriptional control><posttranscriptional regulation><social role><transcription factor><vaccine development>