# Investigating the role of DUX and miR-34a regulation in cell fate plasticity and cancer

> **NIH NIH F30** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $51,752

## Abstract

Project Summary
Hijacked plasticity of cell fate potential, combined with oncogenic mutations, drives malignant transformation and
therapeutic resistance in many cancers. Totipotency – the ability of a cell to become all embryonic and extra-
embryonic tissues – represents the height of embryonic/stem cell fate potential in mammals. DUX is a double
homeodomain transcription factor that is misexpressed in subsets of B-cell acute lymphoblastic leukemia and
round-cell sarcomas. Our lab recently defined DUX (mouse Dux / human DUX4) as a major driver of totipotent
developmental programs in mouse and human. Pluripotent mouse embryonic stem cells (mESCs) expressing
mouse Dux are potently converted into a ‘2C-like’ totipotent state, which epigenetically and transcriptionally
resemble the 2-cell mouse embryo. In vivo, DUX expression is highly transient, and lasts less than a cell cycle
in early embryos. Although the transcriptome of totipotency is well studied, it is unclear how the embryo employs
post-transcriptional and translational regulation downstream of DUX to establish this plasticity in cell fate, and
what mechanisms subsequently restrict developmental potency to ensure proper lineage determination.
Recently, we and others have discovered a central role for p53 in DUX activation. P53 is a master tumor
suppressor and transcription factor, which also activates the micro-RNA (miRNA) 34 family (a/b/c) in response
to DNA damage. miR-34a is expressed in many mouse and human tissues, and is a well-studied tumor
suppressor itself, repressing pathways involved in cellular growth and proliferation. Importantly, miR-34a deletion
in mESCs confers a high probability of their conversion into a totipotent state, however the mechanisms
governing this expanded cell fate plasticity are unclear. We find that loss of miR-34a in mESCs causes
accumulation of Dux transcripts, and DUX4 contains a predicted miR-34a target site in its 3’ UTR, suggesting a
direct regulatory role of miR-34a. We hypothesize that p53 and miR-34a activate and repress Dux (and/or Dux
targets), respectively, forming a feedback loop which regulates the totipotency network and ultimately restricts
cell fate plasticity in vivo. Uncovering the mechanisms safe-guarding cell fate potential and preventing
oncogenesis in vivo will yield novel insights in both cancer biology and regenerative medicine. I am uniquely
positioned to answer these questions in the Cairns Lab within the Huntsman Cancer Institute at the University of
Utah. Leveraging our advanced DUX expertise, combined with key collaborations with experts in translational
control, I am confident in my abilities to execute the experiments outlined within this proposal. Additionally, my
excellent clinical mentorship team, crafted from highly productive physician- and surgeon-scientists, will promote
my clinical development as I seek to combine key insights from molecular drivers of cell fate plasticity and
oncogenesis into development of novel tar...

## Key facts

- **NIH application ID:** 10293564
- **Project number:** 5F30HD098000-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Bradley Don Weaver
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2018-11-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293564

## Citation

> US National Institutes of Health, RePORTER application 10293564, Investigating the role of DUX and miR-34a regulation in cell fate plasticity and cancer (5F30HD098000-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10293564. Licensed CC0.

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