Defining the Regulatory Logic of Breast Cancer Using Single-Cell Epigenetic and Transcriptome Profiling

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Understanding cis-regulatory elements is key to deciphering cancer's transcriptional dysregulation.
• Single-cell resolution of chromatin accessibility and transcriptome is crucial for detailed tumor biology insights.

Purpose of the Study:

• To create a compendium of matched single-cell chromatin accessibility (scATAC-seq) and transcriptome (scRNA-seq) profiles from human breast tumors and healthy tissues.
• To identify the cell-of-origin for luminal and basal breast tumors.
• To develop a novel methodology for quantifying associations between regulatory elements and gene expression in malignant versus normal cells.

Main Methods:

• Single-cell ATAC sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) on fresh human breast tumor and healthy mammary tissue.
• Application of linear mixed-effects models to associate chromatin accessibility with gene expression.
• Generation of matched scATAC-seq and scRNA-seq profiles for breast cancer cell lines.

Main Results:

• Identification of cell-of-origin for luminal and basal breast tumors.
• Discovery of regulatory elements that switch from gene silencing in normal cells to gene enhancement in cancer cells.
• Upregulation of clinically relevant oncogenes due to altered regulatory elements.
• Demonstration of conserved oncogenic gene expression programs in vitro and in vivo across breast cancer subtypes.

Conclusions:

• Non-coding regulatory mechanisms play a significant role in oncogenic processes.
• Single-cell multi-omics effectively defines the regulatory logic of breast cancer cells at single-cell resolution.
• This dataset provides valuable resources for understanding breast cancer biology and developing targeted therapies.