Project description:We measured changes in H3K27ac-marked enhancer contacts before and after treatment of human breast cancer cell lines with abemaciclib
Project description:Here, we combine comparative regulatory genomics with machine learning to investigate enhancer logic in melanoma. Through epigenomics profiling of 26 melanoma cell lines across six species, we examine the conservation of the two main melanoma states and underlying master regulators. By training a deep neural network on topic models derived from the human lines, we were able to classify not only human melanoma enhancers, but also regulatory regions in the other species. The deep learning model revealed important genomic features (i.e. TF binding motifs) for the different melanoma states, how they co-occur within melanoma enhancers, and where they are placed with respect to the central enhancer nucleosome. This in-depth analysis of the melanoma enhancer code allowed us to propose a mechanistic model of TF binding in MEL melanoma enhancers. Finally, by exploiting the deep layers of our model, we are able to identify causal mutations for melanoma enhancer loss and gain through evolution, not only affecting enhancer accessibility but also activity.
Project description:The imbalance of cellular homeostasis during oncogenesis together with the high heterogeneity of tumor-associated stromal cells have a marked effect on the repertoire of the proteins secreted by malignant cells (the secretome). Hence, the study of tumoral secretomes provides insights for understanding the cross-talk between cells within the tumor microenvironment as well as the key effectors for the establishment of the pre-metastatic niche in distant tumor sites. In this context, we performed a proteomic analysis of the secretomes derived from four cell lines: (i) a paired set of fibroblasts - Hs 895. T, a cell line obtained from a lung node metastatic site from a patient who had melanoma and Hs 895.Sk, a skin fibroblast cell line (derived from the same patient); (ii) two malignant metastatic melanoma cell lines - A375, a malignant melanoma cell line from primary source and SH-4, a cell line derived from pleural effusion of a patient with metastatic melanoma. Clustering of expression profiles together with functional enrichment revealed patterns that mirrored each cell type (skin fibroblasts, cancer-associated fibroblasts and metastatic cells). These patterns might be the result of cell-specific protein expression programs and may serve as basis for further proteomic analysis of melanoma cell lines secretomes.