Yang Cheng

Cellular function depends on the spatial organization of cells and biomolecules within the tissue microenvironment. Advances in spatial omics have enabled profiling of molecular features such as transcriptome, proteome and epigenome, and there has been rapid progress of imaging-based approaches to study spatial three-dimensional (3D) genome organization. Here we present Spatial-ATAC-Hi-C, a microfluidic‑based platform for genome-wide, spatially resolved joint-profiling of 3D genome organization and chromatin accessibility on tissue slides. Applied to mouse and human brains, Spatial-ATAC-Hi-C revealed distinct chromatin architecture and gene regulatory programs in neuronal and non-neuronal populations in their native tissue context. In glioblastoma and astrocytoma samples, we detected spatially resolved 3D genome alterations, copy number variations and structural variations across tumor regions, revealing clinically relevant oncogenic events and clonal heterogeneity. By co-profiling of genome architecture and chromatin accessibility while preserving tissue architecture, Spatial-ATAC-Hi-C provides a powerful tool for studying spatial gene regulation in human biology and disease.

Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies. While the overexpression of pioneer factor GATA6 in CRC has been linked with metastasis, its role in genome-wide gene expression dysregulation remains unclear. Through studies of primary human CRC tissues and analysis of the TCGA data, we found that GATA6 preferentially binds at CRC-specific active enhancers, with enrichment at enhancer-promoter loop anchors. GATA6 protein also physically interacts with CTCF, suggesting its critical role in 3D genome organization. The ablation of GATA6 through AID and CRISPR systems severely impaired cancer cell clonogenicity and proliferation. Mechanistically, GATA6 knockout induced global loss of CRC-specific open chromatins and extensive alterations of critical enhancer-promoter interactions for CRC oncogenes. Last, we showed that GATA6 knockout greatly reduced tumor growth and improved survival in mice. Together, we revealed a previously unidentified mechanism by which GATA6 contributes to the pathogenesis of colorectal cancer.