A single-cell multiomics platform for studying genome structure and function

The National Institutes of Health National Human Genome Research Institute awarded the University of Washington $796,114 on September 1, 2026, under the Human Genome Research program (CFDA 93.172) to develop a single-cell multi-omics toolkit for studying genome structure and function.

The award funds expansion of GAGE-SEQ, a scalable single-cell multiomics method, to simultaneously profile three-dimensional genome organization and transcriptome alongside chromatin accessibility, transcription factor binding footprints, and splicing isoforms within individual cells. The recipient will enhance the toolkit's sensitivity and throughput to detect fine-scale chromatin features and implement data processing pipelines and computational tools for integrative analysis of multimodal genomic data. Research will connect multiscale three-dimensional genome features with gene expression in single cells, refine cell subtypes in complex tissues, unveil gene regulatory networks, and analyze three-dimensional genome dynamics during cell differentiation.

The University of Washington Office of Sponsored Programs will administer the award. Work is performed in Seattle, Washington. The period of performance runs through August 31, 2030.

Abstract

The three-dimensional (3D) genome organization in the nucleus is pivotal to various genome functions such as transcription and DNA replication. 3D genome organization works in concert with chromatin accessibility, transcription factor (TF) binding and other epigenetic features of the chromatin to ensure spatiotemporal gene expression during tissue development. However, due to the interdependency between them, IT remains challenging to dissect the intricate interplays between these different regulatory layers of gene expression. We recently developed gage-SEQ, a scalable single-cell multiomic method to simultaneously profile 3D genome and transcriptome in individual cells (zhou ET AL. Nature genetics, 2024). Gage-SEQ helps directly connect multiscale 3D features with gene expression in single cells, refine cell subtypes in complex tissues, unveil gene regulatory networks, and analyze 3D genome dynamics during differentiation. Despite its potential, gage-SEQ and other methods lack the sensitivity and throughput needed to delineate fine-scale chromatin features, chromatin accessibility, TF binding, and transcription regulation at the single-cell level. To address this, we propose to develop a single-cell multi-omics toolkit based on gage-SEQ to advance our understanding of genome structure and function. With the expanded capacity to detect more molecular modalities within a single cell, our new genomic tools will enable US to CO-measure not only multiscale 3D architectural features and transcriptome but also a diversity of other molecular modalities including chromatin accessibility, TF binding footprints, and splicing isoforms within the same cell. In parallel, we will implement data processing pipelines and develop new computational tools for integrative analysis of the multimodal data. To demonstrate the utility of these new tools, we will then apply them to investigating the epigenetic mechanisms underlying the complex hematopoietic malignancies.