Chromatin Landscape of Cancer Cell Lines Identifies Enhancer Subtypes

Mattohti, M.; Arslan, E.; Raman, A.; Terranova, C.; Liu, Z.; Orouji, E.; Srinivasan, S.; Kochat, V.; Tang, M.; Amin, S.; Schulz, J.; Samant, N.; Singh, A.; Martinez-Ledesma, E.; Sarkar, S.; Coyle, M.; Bristow, C.; Johnson, F. M.; Pickering, C. R.; Torres, K.; Rai, K.

doi:10.64898/2026.08.01.741526

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bioRxiv · 10.64898/2026.08.01.741526

Chromatin Landscape of Cancer Cell Lines Identifies Enhancer Subtypes

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Abstract

Epigenetic aberrations are a hallmark of cancer; however, systematic chromatin state maps of cancer cells are unavailable. We generated and analyzed 803 histone mark profiles in 142 cancer cell lines and 114 human tumors belonging to 9 solid tumor types. Irrespective of their cell-of-origin, cancer cells segregate from normal tissues based on their enhancer patterns, suggesting enhancer deregulation is a fundamental epigenetic feature in cancer. Enhancer based clustering defined 5 distinct subgroups of cancer cells (EpiC1-5) with unique developmental trajectories, molecular features and dependencies. Importantly, we define a set of core TFs that are critical for EpiC-specific enhancer patterns and survival. Notably, EpiC4 represented a predominantly epigenetic, pan-cancer subtype that displays poor survival, activation and dependence on a FN1-CAV1-SRC-PI3K-AKT signaling network. Together, these data uncover enhancer heterogeneity in pan-cancer systems with identification of a novel enhancer-based subtype and identify potential new therapeutic targets associated with unique epigenetic features.

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Mattohti, M., Arslan, E., Raman, A., Terranova, C., Liu, Z., Orouji, E., Srinivasan, S., Kochat, V., Tang, M., Amin, S., Schulz, J., Samant, N., Singh, A., Martinez-Ledesma, E., Sarkar, S., Coyle, M., Bristow, C., Johnson, F. M., Pickering, C. R., Torres, K., Rai, K.. 2026-08-04. Chromatin Landscape of Cancer Cell Lines Identifies Enhancer Subtypes. https://doi.org/10.64898/2026.08.01.741526

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