# Characterizing age-associated epigenetic alterations and their roles in tumor development

> **NIH NIH U01** · JOHNS HOPKINS UNIVERSITY · 2020 · $122,813

## Abstract

The goal of this proposal is to characterize in detail the age-associated epigenetic alterations and their functional
roles in the age-related risk for cancer, so that we can devise approaches to either prevent or treat early
neoplasms. This proposal builds on our current ongoing and recently published work indicating that cancers
derive from ageing, dividing cells due to accumulation of epigenetic changes. Multiple studies have shown that
normal ageing involves accumulation of epigenetic alterations involving DNA methylation, modifications to
histone and non-histone proteins, and chromatin structure. However, most studies have focused on DNA
methylation, and the functional roles of these various age-related epigenetic modifications in promoting
tumorigenesis has been lacking. Our work uses novel approaches employing ex vivo colon-derived stem cell
organoid and in vivo mouse models. In preliminary data, we show that “ex vivo ageing” of mouse colon organoids
involves evolution of promoter DNA hypermethylation, akin to in vivo ageing, which facilitates activation of the
Wnt-pathway and predisposes to transformation by oncogenic-Braf. To obtain in-depth insights into alterations
in the transcriptome due to age-associated epigenetic changes, and its impact on tumor initiation, we will map
key histone modifications (H3K4me3, H3K27me3, H3K27ac), DNA methylation and chromatin structure
(open/closed chromatin configuration) in colon epithelial cells from mice of different age groups. Changes to
gene regulation mediated by epigenetic alterations in promoters and other genomic regulatory elements, such
as enhancers, will be identified. The genomic analyses will be followed by functionally testing the roles of
important age-altered genes and pathways in promoting tumor initiation using the novel organoid-based ex vivo
tumorigenesis assays. Importantly, our work focuses on understanding the epigenetic changes in long-lived
colon epithelial stem cells, from which tumors most likely derive. Our current data invokes the concept that
epigenetic events in stem cells, arising in the context of ageing, may initially allow escape from senescence,
retention of stem cell characteristics, and cause differentiation defects. We hypothesize that minor stem cell
subpopulations with such characteristics exist in aged tissues and are predisposed to tumorigenesis in the
context of cancer driver mutations. We will test this hypothesis using ex vivo organoids generated form mice of
different age groups, and enriching for cells with increased stem cell properties/differentiation defects. Finally,
we will directly test if epithelial stem cells from aged organoids are predisposed to tumorigenesis in the context
of oncogenic mutations. In ongoing work we have teamed up with Dr. Rafael de Cabo (NIA); the complementary
expertise of our groups in age-related disorders (de Cabo) and cancer epigenetics (Baylin, Easwaran) will help
achieve the stated goals. Ultimately, our findings using...

## Key facts

- **NIH application ID:** 9926803
- **Project number:** 5U01AG066101-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** STEPHEN B. BAYLIN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $122,813
- **Award type:** 5
- **Project period:** 2019-05-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926803

## Citation

> US National Institutes of Health, RePORTER application 9926803, Characterizing age-associated epigenetic alterations and their roles in tumor development (5U01AG066101-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9926803. Licensed CC0.

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