# The DAXX/ATRX/H3.3 axis in ERV regulation and tumor suppression

> **NIH NIH K22** · UNIVERSITY OF CINCINNATI · 2024 · $130,192

## Abstract

Project Summary
Genome sequencing has implicated novel candidate tumor suppressors, including DAXX and ATRX which are
mutated in 43% of pancreatic neuroendocrine tumors (PanNETs). Despite this strong disease association, our
understanding of the physiological functions of DAXX and ATRX remains limited. Biochemical and cell
biological studies have demonstrated that together they regulate the epigenome as a chaperone complex for
the histone variant H3.3, depositing H3.3 in heterochromatin. Additional non-histone chaperone functions have
been reported for both genes. We recently developed a conditional mouse model for Daxx and demonstrated
that Daxx loss creates a permissive state that cooperates with environmental stress (inflammation) and other
genetic lesions (Men1 loss) to affect the transcriptional profile and impact cell state, which ultimately impairs
pancreas recovery and regeneration in vivo. The transcriptional changes are associated with dysregulation of
ERVs, thereby expanding our understanding of the somatic regulation beyond DNA and histone methylation in
vivo, and implicating ERV dysregulation of pancreatic neuroendocrine tumorigenesis. Importantly, we also
demonstrated that dysregulation of endogenous genes near ERVs is also observed in human PanNETs with
DAXX mutations. This proposal expands on these studies to better understand how mutations in DAXX
contribute to tumorigenesis. We will first use our robust physiological mouse models to obtain a comprehensive
understanding of the epigenetic mechanisms that underlie ERV dysregulation downstream of Daxx loss. We
will conduct an integrative analysis of H3.3 incorporation, DNA methylation, and histone methylation. We will
complement these genomic studies with genetic experiments to directly interrogate the Daxx:H3.3 and
Daxx:Atrx interactions in vivo using newly generated mouse alleles. Finally, we will extend our studies to an
innovative human pluripotent stem cell model that can be differentiated to an endoderm lineage and
subsequent pancreas and endocrine cell states. This will reveal context-dependent effects of DAXX loss and
illuminate the specific downstream changes that contribute to tumorigenesis. The K22 Career Transition award
will not only advance these research objectives, but it will also help achieve my long-term career goal of
directing a productive and impactful independent research program focused on the molecular mechanisms that
underlie tumorigenesis. Specifically, it will support the establishment of my independent laboratory at a new
sponsoring institution. It will further allow for the submission of my first senior author manuscript and provide
the foundations and preliminary data to rapidly apply and be competitive for R01 funding. In summary, this
proposal supports both research and career development in the epigenetic regulation of cellular homeostasis
and how dysregulation contributes to pancreatic neuroendocrine tumorigenesis.

## Key facts

- **NIH application ID:** 10771092
- **Project number:** 5K22CA258674-03
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Amanda Rietta Wasylishen
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $130,192
- **Award type:** 5
- **Project period:** 2022-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771092

## Citation

> US National Institutes of Health, RePORTER application 10771092, The DAXX/ATRX/H3.3 axis in ERV regulation and tumor suppression (5K22CA258674-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10771092. Licensed CC0.

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