# Charting the 3D epigenome in human brain development and diseases

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $180,000

## Abstract

Project Summary/Abstract
A key tenet of the 4DN project is that nuclear functions (e.g., gene expression) is directly influenced by the spatial
organization of the genome, not only in relation to the 1D sequence distance between chromosomal regions but
also with respect to their three-dimensional spatial organization in the nucleus. While there has been substantial
progress in our understanding of the functional implications of the relative proximity of genomic loci in terms of
their three-dimensional spatial distance through sequencing-based (e.g., Hi-C) and imaging-based (e.g.,
Multiplexed FISH) omics data, the functional implications of the dynamic positioning of loci within the nuclear
topography (i.e., the volumetric mapping of loci with respect to the nuclear microenvironment) remains a more
challenging task. In particular, because systematic evaluation of the functional role of the nuclear topography in
health and disease requires the effective integration of sequencing-based and imaging-based omics data from
multiple different tissue types, biological statuses, conditions, and laboratories. This goal requires the
development of standardized nuclear reference coordinate systems in which spatial data from different sources,
often varying largely in nuclear shape, is first mapped against common nuclear landmarks and then integrated
into one Common Coordinate Framework (CCF). Here we propose to establish guidelines for the 4DN Nuclear
CCF and define methods for mapping the location of nuclear boundaries across different experimental systems
and assess the opportunity and feasibility of different experimental methods. We will produce benchmarking
Multiplexed FISH datasets to evaluate different nuclear boundary visualization approaches identified on the basis
of current user practices and will suggest methods that are minimally detrimental to the productivity of
experimental laboratories. Our proposal will expedite the development of a cross-consortium 4DN nuclear CCF
capable of univocally mapping the location of FISH Omics imaged target genomic segments with respect to the
NE, nuclear bodies, the center of the nucleus, and each other in a manner that can then be used to integrate
data across different experimental contexts and will allow incorporation in integrated predictive modeling
frameworks. In summary, by directly addressing the functional significance of nuclear topography on nuclear
function, a CCF would make 4DN-produced imaging data more valuable for computational scientists and for the
community at large.

## Key facts

- **NIH application ID:** 10887266
- **Project number:** 3U01DA052713-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ARNOLD KRIEGSTEIN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $180,000
- **Award type:** 3
- **Project period:** 2020-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887266

## Citation

> US National Institutes of Health, RePORTER application 10887266, Charting the 3D epigenome in human brain development and diseases (3U01DA052713-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10887266. Licensed CC0.

---

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