# Sequence models of genome regulatory architecture in 3D

> **NIH NIH DP2** · UNIVERSITY OF CHICAGO · 2024 · $684,677

## Abstract

Project Summary
Interpreting individual genome sequence and the consequence of any sequence variation is critical for the study of
the genetic basis of diseases and the path toward precision medicine. Genomic sequence is at the basis of
multiple levels of genome regulation which are highly intertwined, including chromatin protein binding, 3D genome
architecture, and gene transcription. Decoding these regulatory functions directly from the sequence will provide a
computational platform for scalable prediction of variant effects and interrogation of base pair-level sequence
functions with “in silico mutagenesis”. Progress has been made in decoding regulatory genomic sequence,
including with the development of deep learning sequence models. However, the sequence-basis of complex
phenomena such as transcriptional regulation will not be fully resolved without accounting for genome structure
and long-range 3D sequence context. Genome structures at multiple spatial scales, including promoter- enhancer
interactions, transcriptional condensates, topologically associating domains, chromatin compartments, and nuclear
bodies can have strong impacts on transcriptional regulation. With data and techniques that have only now
become sufficient to tackle this challenge, we will study these phenomena and trace complex regulatory output back
to the basis of sequence dependencies by developing sequence models of 3D genome regulatory architecture.
We will develop a computational framework of deep learning sequence models with the capability of modeling
multiscale 3D genome interactions and integrating long-range sequence information, for comprehensively
interpreting the regulatory functions of genome sequence. The proposed work will open up new possibilities for
interpreting and applying structural and transcriptional impacts of sequence variations, including asking how
genetic factors, such as large structural variants, affect gene expression through remodeling of genome structural
organization in healthy and disease states.

## Key facts

- **NIH application ID:** 11430672
- **Project number:** 7DP2GM146336-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Jian Zhou
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $684,677
- **Award type:** 7
- **Project period:** 2021-09-23 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11430672

## Citation

> US National Institutes of Health, RePORTER application 11430672, Sequence models of genome regulatory architecture in 3D (7DP2GM146336-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11430672. Licensed CC0.

---

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