# Sequence models of genome regulatory architecture in 3D

> **NIH NIH DP2** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $1,476,000

## 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:** 10242561
- **Project number:** 1DP2GM146336-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Jian Zhou
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,476,000
- **Award type:** 1
- **Project period:** 2021-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242561

## Citation

> US National Institutes of Health, RePORTER application 10242561, Sequence models of genome regulatory architecture in 3D (1DP2GM146336-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10242561. Licensed CC0.

---

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