# Pan-disease characterization of DNA methylation dysregulation

> **NIH NIH K99** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $173,794

## Abstract

DNA methylation is an important epigenetic mark with a regulated pattern in healthy tissues. Disruption of this
pattern, called methylation dysregulation, has been reported in many diseases including cancer, autoimmune
diseases, metabolic and psychological disorders, and diseases related to aging. Importantly, methylation
dysregulation has been observed in pre-disease states and the degree of dysregulation correlates with disease
severity and also response to treatment. These observations compel the study of methylation dysregulation
because it may reveal common origins of human disease, and because genomic elements (e.g. genes,
mutations, and regulatory features) associated with methylation dysregulation may be potential targets for
diagnostic and early intervention therapies. However, the genomic elements that control and maintain
methylation dysregulation have not been well-characterized. Understanding the mechanisms and pathways
that are responsible for the establishment of epigenetic dysregulation is critical for understanding the
establishment of the disease phenotype in general. We hypothesize that specific genomic elements could
contribute to methylation dysregulation in reproducible ways across diseases.
This research seeks to identify genomic elements that may initiate a disease state that is common across
multiple diseases. This will be accomplished by the development of computational algorithms to leverage and
integrate patient samples from many diseases, as well as the development of a new high-throughput genomic
screen. Specifically, we propose the following specific aims:
(1) Identification of genes associated with methylation dysregulation using a pan-disease machine-learning
approach;
(2) Exploration of the contribution of the noncoding genome to methylation dysregulation through analysis of
 genome variants and chromatin accessibility data;
(3) Development and validation of a novel CRISPR screen to link gene perturbations to methylation
 landscapes in a high-throughput manner.
In summary, completion of these aims will produce an in-depth characterization of the genomic elements
associated with methylation dysregulation, leading to understanding of the processes and mechanisms of
epigenetic dysregulation. More broadly, the proposed analysis framework and computational approach will
explore the utility of integrative pan-disease studies to identify common characteristics of disease which could
lead to diagnostic and therapeutic solutions. This proposal takes advantage of the applicant's expertise in
genetics, genomics, and high-throughput assays. It also includes training and research experience in
experimental design and execution which will advance the candidate's goal of becoming an independent
research scientist capable of investigating genome function, specifically the genomic origins of human disease.

## Key facts

- **NIH application ID:** 10404524
- **Project number:** 5K99HG011658-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Kendell Clement
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $173,794
- **Award type:** 5
- **Project period:** 2021-05-12 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404524

## Citation

> US National Institutes of Health, RePORTER application 10404524, Pan-disease characterization of DNA methylation dysregulation (5K99HG011658-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10404524. Licensed CC0.

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