3D Chromatin Rewiring During Melanoma Phenotypic Transition - Pietro Berico

Melanoma intra-tumor heterogeneity is thought to be the root cause of cancer progression and therapy resistance. Melanoma cells can transiently “switch” between different transcriptional states or phenotypes as an adaptive response to microenvironmental cues. Genetic studies in patient cohorts, cell lines and melanoma mouse models have failed to identify drivers of phenotype transition, suggesting that epigenetic deregulation may be primarily responsible for those switches. The melanoma lineage-specific transcription factor MITF plays a key role, with high MITF activity associated with a proliferative melanocytic-like phenotype, while low activity leads to a more invasive mesenchymal-like phenotype. However, MITF silencing or ectopic expression alone are insufficient to trigger a complete phenotype transition, suggesting that other epigenetic factors are required. Chromatin is folded in the nucleus in three dimensional hierarchical structures that increase or decrease enhancer-promoter contact loops to regulate gene expression in a space and time fashion. Alterations in 3D chromatin architecture can contribute to cancer. Still, the molecular factors governing global nuclear topology and its contribution to melanoma phenotypic plasticity are completely unknown. Using “all-vs-all” chromosome conformation capture (Hi-C), we profiled the global 3D chromatin architecture of a large panel of melanoma cell lines representative of distinct phenotypic states and at different time points post-MITF silencing. Analyzing different levels of hierarchical chromatin structures, we observed that MITF alone is unable to modulate topological associated domains (TADs) and major hierarchical structures. On the contrary, we observed a dramatic increase in cis-long contact loops and a decrease of TADs in mesenchymal-like melanoma cells relative to melanocytic, suggesting mesenchymal-like cells may bear a more “flexible” chromatin. In line with this evidence, we are currently testing whether, together with MITF loss, adding mechanical pressure to the nuclei and/or microenvironmental stiffness is required to fully refold the chromatin and allow phenotypic transition. By combining epigenetic and mechanical perturbations on melanoma cells, we aim to demonstrate the novel role of chromatin architecture in driving phenotypic state transitions.
Pietro Berico, PhD
Dr. Berico is a Postdoctoral Fellow in Prof. Eva Hernando-Monge’s lab at NYU Grossman School of Medicine. His studies aim to understand how different levels of gene expression regulation, including 3D chromatin organization, transcription factor activity, and epigenetic modulation of non-coding RNAs can drive melanoma phenotypic plasticity underpinning tumor initiation and progression.
The Monthly Seminar on Physical Genomics is sponsored by the Center for Physical Genomics and Engineering at Northwestern University, the Cancer and Physical Sciences Program at the Robert H. Lurie Comprehensive Cancer Center, and NIH Grants T32GM142604 and U54CA268084
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