# Elucidating the impact of DNA hypomethylation on genome organization and anti-tumor transcriptional programs

> **NIH NIH K08** · DANA-FARBER CANCER INST · 2021 · $108,083

## Abstract

PROJECT SUMMARY
This proposed research career development program seeks to investigate the impact of DNA
hypomethylation on genome organization and the mechanisms by which it drives downstream
tumor suppressive transcriptional programs. The candidate is currently a clinical and research
fellow in the Department of Pathology of the Massachusetts General Hospital. The proposal
incorporates specific technical skills that will be required for the project including training in
advanced microscopy methods, CRISPR techniques and repetitive element biology. The structured
career development plan includes training and mentorship in laboratory management, scientific
leadership, research communication, grant writing, and other critical career skills. These technical
and career skills will be acquired under the guidance of Dr. Bradley Bernstein, who will serve as
primary mentor and has a history of trainees that obtain group leader positions in academia, as
well as a Research Advisory Committee of world-class scientists including Drs. Kathleen Burns,
Ting Wu, Keith Joung and Nir Hacohen. Through this comprehensive program the candidate will
acquire a unique set of clinical and research skills that will enable her to transition to an
independent physician scientist faculty position with a lab focused on basic mechanisms and
therapeutic opportunities in cancer epigenetics.
DNA hypomethylation is an epigenetic alteration found in most solid tumors, but its functional
consequences are not clearly defined. DNA demethylating therapies are widely used in the clinic
for treatment of myelodysplastic syndrome and a subset of leukemias, and have recently been
shown to sensitize tumor cells to immunotherapy, possibly through activation of ERVs. Despite
this, the functional consequences of DNA hypomethylation and ERV activation remain obscure.
This project explores the mechanistic basis of findings in the candidate’s recent study of genome
organization in primary colon tumors. The results link DNA hypomethylation to striking changes in
the organization of chromatin compartments that are associated with tumor suppressive
transcriptional programs, including induction of ERVs. The aims of this proposal are to: (1)
Investigate if DNA hypomethylation causes chromatin reorganization, (2) test if massive ERV
upregulation is a mechanistic link between hypomethylation and compartment reorganization and
(3) determine impact of downstream transcriptional programs. These studies will uncover novel
epigenetic mechanisms that impact tumor cell identity and lay the foundation for deploying
demethylating therapies in new clinical settings to harness tumor-suppressive consequences of
DNA hypomethylation.

## Key facts

- **NIH application ID:** 10457023
- **Project number:** 7K08CA259623-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Sarah E Johnstone
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $108,083
- **Award type:** 7
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457023

## Citation

> US National Institutes of Health, RePORTER application 10457023, Elucidating the impact of DNA hypomethylation on genome organization and anti-tumor transcriptional programs (7K08CA259623-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10457023. Licensed CC0.

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