# Genetic Modifier Activity and Network Properties of Nxf1

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $400,451

## Abstract

Abstract
Gene expression networks typically evolve multiple layers of regulatory coordination to
facilitate coherent response to developmental, physiological or environmental conditions.
Transposition of mobile elements, including endogenous retroviruses, has been
hypothesized to create or modify gene regulatory networks, particularly through effects
on transcriptional initiation. Some elements are also known that affect alternative RNA
processing events, potentially allowing post-transcriptional coordinating mechanisms
that may be subject to natural selection. We previously showed that the major allele of
nuclear export factor Nxf1 in Mus musculus castaneus mice is a semi-dominant
suppressor of de novo mutations caused by insertion of intracisternal A particle (IAP)
endogenous retroviruses into host gene introns, by mitigating IAP-induced alternative
RNA processing. The molecular phenotype of Nxf1-mediated suppression includes both
an increased level of correctly processed host gene transcript and a decrease in virus-
induced alternative forms. This was unexpected, as biochemical data for Nxf1 suggest
that its major activity is export of ribonucleoprotein particles after completion of RNA
processing. However, many viruses also attack Nxf1 to promote viral gene expression
over that of the host. The genetic modifier activity of Nxf1 resides in a single amino acid
substitution, E610G, that appears to be under positive directional selection in wild mice
and that coordinately affects several IAP-inserted host genes in laboratory mice. These
results suggest unexpected mechanisms by which Nxf1 regulates gene expression
beyond its known role in export. Several Nxf1 binding partners are known to influence
transcriptional elongation rate in other contexts and elongation rate influences alternative
RNA processing steps. To understand the mechanism and the unexpected plasticity in a
pathway that is conserved among animals and fungi, we propose three aims. (1) We will
test the interdependence of suppression, elongation rates, and epigenetic marks related
to elongation and retroviral silencing. (2) We will determine the effect of suppressing
Nxf1 variants on protein complex formation both in intact cells and in simplified in vitro
assays and test the role of variant partners in regulated suppression. (3) We will quantify
the effects of each Nxf1 residue on cell viability, genetic suppression, and interactions
with key partners using a deep mutational scanning approach.

## Key facts

- **NIH application ID:** 9837446
- **Project number:** 5R01GM086912-18
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** BRUCE A HAMILTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,451
- **Award type:** 5
- **Project period:** 1998-12-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837446

## Citation

> US National Institutes of Health, RePORTER application 9837446, Genetic Modifier Activity and Network Properties of Nxf1 (5R01GM086912-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9837446. Licensed CC0.

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