# Beyond Gene Dosage: Understanding Down Syndrome via 4D Genome Organization

> **NIH NIH U01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $638,318

## Abstract

ABSTRACT
Chromosomal aneuploidy underlies a variety of human diseases. The most prominent paradigm among these
is Down syndrome (DS) that is caused by an extra copy of homo sapiens chromosome 21 (HSA21). As the
most common genetic disease of human cognitive impairment, DS affects about 1 in 750 live-born infants in
the US, and it pre-disposes patients to muscle hypotonia, dysmorphic features, congenital heart defects and
early onset Alzheimer's disease. Despite many progress, our conceptual understanding of the pathological
basis of such chromosomal abnormality is so far largely limited to the “gene dosage hypothesis”, which
however cannot explain broad gene deregulation that takes place throughout the genome in specific cell types.
It has been unexplored that whether 3D genome mal-folding may play yet unrealized roles in DS and other
aneuploidies. Here, we assembled a strong team to test an overall hypothesis that the presence of trisomy 21
deregulates 3D genome as an entirety and changes gene expression in DS cells, particularly via forming
aberrant inter-chromosomal interactions (ICIs). We have two specific aims. In Aim-1, in multiple pairs of
isogenic iPSC cells and their derived neuron/glia cells that contain disomic versus trisomy HSA21, we will
conduct assays to systematically characterize their 3D genome (in situ Hi-C and PLAC-Seq), transcriptome
and 1D epigenome (PRO-Seq, ATAC-Seq, and histone modification ChIP-Seq). Integrative analyses will
dissect the aberrant chromatin interactomes, particularly these interchromosomal interactions altered in trisomy
nucleus, and correlate those with gene deregulation in specific developmental stages or cell types (neurons,
astrocytes or microglia). We will use leading-edge new techniques based on long reads sequencing to further
characterize aberrant inter-chromosomal interactions, and will validate them using DNA and/or RNA FISH. In
Aim-2, we focus on functionally dissecting the roles of aberrant inter-chromosomal interactions in gene
deregulation. This will be first investigated by chemical and epigenetic perturbation in both cultured primary
neural progenitor cells and in brain cortical organoids. We will then use novel optogenetic tools to model
disease-relevant formation of ICIs to deduce their potential causal roles in gene deregulation. The expected
results from this proposal are significant not only to our understanding of the 4D genome, but also to human
brain developmental disorders. The knowledge generated here will shed light on many forms of aneuploidy,
providing a new conceptual framework beyond “gene dosage effects” to understand gene deregulation, and
inspire strategies to ameliorate these diseases via restoring 3D genome architecture.

## Key facts

- **NIH application ID:** 10117780
- **Project number:** 1U01HL156059-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Wenbo Li
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $638,318
- **Award type:** 1
- **Project period:** 2020-09-18 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117780

## Citation

> US National Institutes of Health, RePORTER application 10117780, Beyond Gene Dosage: Understanding Down Syndrome via 4D Genome Organization (1U01HL156059-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10117780. Licensed CC0.

---

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