# From epigenome to genome and back: disentangling the relationship between epigenetic modifications and chromatin organization

> **NIH NIH R35** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $377,555

## Abstract

PROJECT SUMMARY
Understanding how the genome functions is one of the greatest challenges of the 21st century. Encoded within
its DNA sequences are the blueprints for several cell types. Nevertheless, it remains a mystery how the full
variety of phenotypes arise, and how they are maintained. It is becoming increasingly clear that the epigenome—
covalent modifications to the DNA and histone proteins—plays a crucial role. Genome-wide profiling of
epigenetic modifications has clarified cell type specificity and the presence of a diverse set of combinatorial
patterns that are strongly correlated with gene expression levels. Inferring causal relationships from these data
has proved challenging, however. A working knowledge of the mechanisms that inform the establishment and
regulation of the epigenome, and its impact on gene expression and cellular phenotype, therefore, remain
elusive. In this project, we propose several novel modeling approaches which will address the key gaps in our
understanding of the interrelationship between the epigenome and genome. First, we will parameterize a coarse-
grained chromatin model from the bottom-up using a novel deep learning algorithm to generate an accurate and
comprehensive characterization of chromatin secondary structure, and its sensitivity to DNA sequence,
nucleosome repeat length, ionic concentrations, post-translational modifications, and phase-separated liquid-
droplets formed by intrinsically disordered proteins. High resolution chromatin structures from this effort will
elucidate how different epigenetic modifications impact gene expression by regulating nucleosome packaging
and DNA accessibility. Second, we will investigate the role of epigenetic modifications in mediating long-range
interactions between regulatory elements by developing a predictive model which will enable de novo
reconstruction of three-dimensional genome organization. This project will result in a global view of the role of
the epigenome in cell differentiation and cell fate determination. An improved understanding of the
interrelationship between the epigenome and the genome from this research program can guide the
development of engineering approaches to modify the epigenome for both long lasting and reversible changes
as a novel strategy for combating diseases such as cancer.

## Key facts

- **NIH application ID:** 10178047
- **Project number:** 5R35GM133580-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Bin Zhang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,555
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10178047

## Citation

> US National Institutes of Health, RePORTER application 10178047, From epigenome to genome and back: disentangling the relationship between epigenetic modifications and chromatin organization (5R35GM133580-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10178047. Licensed CC0.

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