| Popis: |
Regulatory networks containing enhancer to gene edges define cellular state and their rewiring is a hallmark of cancer. While efforts, such as ENCODE, have revealed these networks for reference tissues and cell-lines by integrating multi-omics data, the same methods cannot be applied for large patient cohorts due to the constraints on generating ChIP-seq and three-dimensional data from limited material in patient biopsies. We trained a supervised machine learning model using genomic 3D signatures of physical enhancer-gene connections that can predict accurate connections using data from ATAC-seq and RNA-seq assays only, which can be easily generated from patient biopsies. Our method overcomes the major limitations of correlation-based approaches that cannot distinguish between distinct target genes of given enhancers in different samples, which is a hallmark of network rewiring in cancer. Our model achieved an AUROC (area under receiver operating characteristic curve) of 0.91 and, importantly, can distinguish between active regulatory elements with connections to target genes and poised elements with no connections to target genes. Our predicted regulatory elements are validated by multi-omics data, including histone modification marks from ENCODE, with an average specificity of 0.92. Application of our model on chromatin accessibility and transcriptomic data from 400 cancer patients across 22 cancer types revealed novel cancer-type and subtype-specific enhancer-gene connections for known cancer genes. In one example, we identified two enhancers that regulate the expression of ESR1 in only ER+ breast cancer (BRCA) samples but not in ER-samples. These enhancers are predicted to contribute to the high expression of ESR1 in 93% of ER+ BRCA samples. Functional validation using CRISPRi confirms that inhibition of these enhancers decreases the expression of ESR1 in ER+ samples. |
