# Gene regulatory network modeling of disease-associated DNA methylation perturbations

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $777,925

## Abstract

PROJECT SUMMARY
Somatic mutations in DNMT3A and TET2 are common in the hematopoietic lineages of elderly individuals,
estimated to affect more than 10% of adults over the age of 65. These mutations increase the risk for
age-related comorbidities, including severe infection, atherosclerotic cardiovascular disease, osteoporosis,
chronic kidney disease and hematologic malignancies, nearly doubling the mortality rate of affected individuals.
DNMT3A and TET2 encode enzymes essential for remodeling DNA methylation during cellular differentiation.
Animal studies suggest that mutations in these genes drive aberrant activation of immune cells, such as
macrophages, which may underlie the disease associations. We recently developed a human pluripotent stem
cell (hPSC)-derived macrophage model, where the differentiation-dependent effects of DNMT3A or TET2
perturbation can be precisely delineated. We discovered that DNMT3A- and TET2- perturbations impaired
DNA methylation remodeling at thousands of regulatory loci, altering enhancer activities and expression of
genes important for macrophage function. Our study highlighted the need for engineering approaches, and
mathematical modeling in particular, to unravel the complex effects of DNMT3A and TET2 perturbations on
cellular function and disease risk.
Here, we pair novel computational modeling approaches with unique experimental resources to
mechanistically connect site-specific changes in DNA methylation to aberrant immune responses and disease
risk. Aim 1 builds deep neural network models (and requisite training data resources) to predict the effects of
DNA methylation on chromatin binding of 100+ transcription factors (TFs), the “readers” of DNA methylation
patterns that ultimately recruit RNA polymerase and co-activators to drive gene transcription. In Aim 2, we
predict genome-scale TF-binding patterns from chromatin accessibility, transcriptional activity and DNA
methylation data in our contexts of interest: DNMT3A- or TET2-perturbed human macrophages in response to
viral and bacterial infection-induced immune activation. To discover links between existing and novel disease
associations, we will intersect the TFBS predictions with curated sets of age-related disease risk variants, to
nominate TFs and contexts where DNMT3A- or TET2-perturbation and downstream alterations in TF binding
might mediate disease risk. In Aim 3, we will construct gene regulatory network (GRN) models of DNMT3A-
and TET2-perturbed human macrophage to identify TFs driving differential gene expression responses to
infection, hypotheses that (1) we will experimentally test and (2) could eventually lead to therapies that mitigate
the negative, pathogenic consequences of common DNMT3A and TET2 mutations. Furthermore, we build
significant generalizable resources (models, modeling methodologies and training data) that will enable future
discoveries in new cell types and disease contexts where alterations in DNA methylation drive phenotype...

## Key facts

- **NIH application ID:** 10845656
- **Project number:** 5R01AI173314-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Minji Byun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $777,925
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845656

## Citation

> US National Institutes of Health, RePORTER application 10845656, Gene regulatory network modeling of disease-associated DNA methylation perturbations (5R01AI173314-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10845656. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*