# Impact of genetic variants on gene regulation and 3D genome organization in human diseases

> **NIH NIH R35** · NORTHWESTERN UNIVERSITY · 2021 · $395,000

## Abstract

PROJECT SUMMARY / ABSTRACT
Genome-wide association studies (GWAS) have discovered thousands of genetic variations that are
associated with hundreds of complex human diseases. However, the underlying mechanisms of how these
variants contribute to disease pathogenesis remain obscure. One of the main hurdles is that the majority of
disease-associated variants identified are located in the non-coding regions, whose annotations and functions
are traditionally poorly understood. Thanks to recent efforts by the ENCODE and Epigenome Roadmap
projects, we have identified millions of potential non-coding regulatory elements in the human genome, mainly
based on high-throughput assays such as DNase-Seq or ChIP-Seq data. More importantly, it has been shown
that 77% of the disease-associated SNPs are located within a potential regulatory region. However, there have
been very few studies in which functional experiments were properly performed to elucidate how SNPs can
disrupt the function of a distal regulatory element and influence the phenotypes.
 Another daunting task is how to identify target genes for the distal regulatory elements that harbor the
disease-associated SNP. This is a challenging problem because enhancers can work from either upstream or
downstream of their target genes, and can be located as far as 1 million base pairs away and still function
through chromatin looping. High-throughput methods based on Chromatin Conformation Capture (3C) have
emerged (such as Hi-C and ChIA-PET, and Capture Hi-C) and represent an unprecedented opportunity to
study higher-order chromatin structure genome-wide. However, data analysis and interpretation for 3C types of
data are still in their early stages, and the complex relationship between chromatin interactions and gene
regulation has just started to be unraveled. The mechanisms of how TADs, sub-TADs and domain boundaries
are formed remains unclear. On the other hand, the impact of 3D structure on gene transcript and epigenetic
landscape is also largely unknown and whether they are the cause or the consequence of 3D genome
structure is yet to be explored as well.
 Given the aforementioned challenges and my unique multi-disciplinary training, my long-term goal is to
use a combination of high throughput genomic experiments, computational modeling, and functional assays to
address the following fundamental questions: 1) How to identify non-coding causal variants for human
diseases? 2) What is the molecular mechanism for the formation of 3D genome organization? 3) What is the
impact of 3D genome organization on gene regulation and human diseases? The proposed work will deepen
our understanding on how genetic variants contribute to gene regulation, 3D genome organization and
molecular mechanisms underlying human diseases.

## Key facts

- **NIH application ID:** 10225400
- **Project number:** 5R35GM124820-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Feng Yue
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,000
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225400

## Citation

> US National Institutes of Health, RePORTER application 10225400, Impact of genetic variants on gene regulation and 3D genome organization in human diseases (5R35GM124820-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10225400. Licensed CC0.

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