# Epigenetic mechanisms of tumor formation in Beckwith-wiedemann Syndrome

> **NIH NIH R03** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $79,250

## Abstract

Beckwith-Wiedeman Syndrome (BWS) is a fetal overgrowth disorder which confers high risk for pediatric
cancers. Loss of DNA methylation (LOM) in a key regulatory region of the KCNQ1 domain resulting in silencing
of a critical cell cycle inhibitor, CDKN1C, occurs in a large group of patients. However, it is unknown how
methylation is disrupted, how it affects other chromatin features and how it leads to tumor development. Thus,
BWS provides a useful paradigm for addressing epigenetic dysregulation in cancer and offers an
opportunity to test novel epigenetic therapeutic strategies. We will perform conformational, epigenetic and
expression studies to determine the status of known promoters, enhancers and insulators and to identify novel
regulatory sequences in the human KCNQ1 domain. We will also perform comparative analyses between
normal fibroblasts and cells from BWS patients exhibiting LOM with co-occurring deletions. These
comparisons will elucidate how LOM affects expression of critical genes in carcinogenesis and explain how the
sequences spanned by patient deletions affect conformation and DNA methylation. We will engineer similar
deletions in normal fibroblasts and epigenetically engineer normal cells to demethylate the DNA sequences
affected in BWS. In addition, we will exploit epigenetic fusion proteins to rescue the epigenetic and
transcriptional profiles of the patient cells. Because current epigenetic therapies act in a genome-wide manner,
successful modification of specific loci with epigenetic editors portends a highly targeted therapy applicable to
any cancer with deregulated gene expression.

## Key facts

- **NIH application ID:** 9968174
- **Project number:** 5R03CA230813-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** NORA I ENGEL
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $79,250
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968174

## Citation

> US National Institutes of Health, RePORTER application 9968174, Epigenetic mechanisms of tumor formation in Beckwith-wiedemann Syndrome (5R03CA230813-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9968174. Licensed CC0.

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