# Constructing High-Resolution Ensemble Models of 3D Single-Cell Chromatin Conformations of eQTL Loci from Integrated Analysis of 4DN-GTEx Data towards Structural Basis of Differential Gene Expression

> **NIH NIH R03** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $309,427

## Abstract

Program Director/Principal Investigator (Liang, Jie):
PROJECT SUMMARY/ABSTRACT
To enhance the utility of the common fund supported 4D Nucleome (4DN) database and Genotype-
Tissue Expression (GTEx) database, we will develop novel computational tools for infering the spatial
organizations of genomic elements to elucidate how eQTLs can regulate the expression of their target
genes. Our tools will integrate 4DN and GTEx data and overcome the limit of the 2D nature of Hi-C
frequency heatmaps, enabling construction of large 3D ensembles of high-resolution models of
single-cell chromatin conformations for loci containing tissue-specific genetic variants associated with
differential expression. By accounting for 3D polymer effects of random collision between genomic
elements due to nuclear volume confinement, our tools will identify chromatin interactions that are
statistically significant and likely biologically important. With the ensemble model of single-cell 3D
chromatin conformations, our tools will further identify participating genes, promoters, enhancers, and
other elements, and elucidate how they are physically arranged in space around genetic variants
associated differential gene expression, including how units of higher order many-body interaction for
gene regulation may form. In addition, our tools will quantify the presence of heterogeneous
subpopulation of cells with different chromatin 3D configurations, allowing probabilistic understanding
of the heterogeneous physical interactions around eQTLs. With planned comparative analysis of 3D
chromatin conformations from different tissues, different spatial pattern of arrangement of genes and
elements important for gene expression will be uncovered, resulting better understanding of genome
structure and function relationship. Overall, we will demonstrate significant added-power of
integrating two important Common Fund data resources and will provide tools to facilitate
understanding the relationship between genome topology and gene expression. Our work will enable
highly specific and compelling testable hypothesis on mechanisms of gene regulation to be
formulated based on the reconstructed 3D spatial genome topology at loci that harbor variants and
eGenes. Validation or refutation of these hypotheses will lead to new insight into the relationship of
genome structure and genome function important for improving human health.
0925-0001 (Rev. 03/16) Page Continuation Format Page

## Key facts

- **NIH application ID:** 10357063
- **Project number:** 1R03OD032628-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Jie Liang
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $309,427
- **Award type:** 1
- **Project period:** 2021-09-22 → 2023-09-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10357063

## Citation

> US National Institutes of Health, RePORTER application 10357063, Constructing High-Resolution Ensemble Models of 3D Single-Cell Chromatin Conformations of eQTL Loci from Integrated Analysis of 4DN-GTEx Data towards Structural Basis of Differential Gene Expression (1R03OD032628-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10357063. Licensed CC0.

---

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