Characterizing heterogeneous cis-regulatory elements in gene regulatory programs associated with breast cancer

Area of Science:

• Genomics
• Epigenetics
• Cancer Biology

Background:

• Cis-regulatory elements (CREs) are crucial for oncogene expression and cancer phenotypes.
• Tumor heterogeneity, a key challenge in cancer, is linked to CRE variations.
• Characterizing cancer-associated CREs is complex, necessitating advanced analytical methods.

Purpose of the Study:

• To map the multicellular ecosystem of breast cancer (BC).
• To identify candidate cis-regulatory elements (cCREs) associated with BC.
• To investigate the role of CRE heterogeneity in intra- and inter-tumor diversity.

Main Methods:

• Performed single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq) on 38 clinical breast cancer samples.
• Utilized marker gene accessibility and single-cell RNA sequencing integration for cell annotation.
• Identified differentially accessible cCREs (DA-cCREs) and constructed enhancer-promoter networks.

Main Results:

• Profiled chromatin accessibility in 22,775 single cells from breast cancer samples.
• Identified 224,585 candidate cis-regulatory elements (cCREs) across the BC ecosystem.
• Demonstrated that enhancer accessibility varies within and between tumors, revealing significant regulatory heterogeneity.

Conclusions:

• This research offers a valuable dataset for future breast cancer epigenetics studies.
• The findings highlight the diverse cis-regulatory landscape within and among tumors.
• cis-regulatory elements (CREs) are implicated as key regulators of intra- and inter-tumor heterogeneity in breast cancer.