Interlocking host and viral cis-regulatory networks drive Merkel cell carcinoma
Lingling Miao, David Milewski, Amy Coxon, Tara Gelb, Khalid A. Garman, Jadon Porch, Arushi Khanna, Loren Collado, Natasha T. Hill, Kenneth Daily, Serena Vilasi, Danielle Reed, Tiffany Alexander, Gabriel J. Starrett, Maharshi Chakraborty, Young Song, Rachel Choi, Vineela Gangalapudi, Josiah Seaman, Andrew Morton, Klaus J. Busam, Christopher R. Vakoc, Daniel J. Urban, Min Shen, Matthew D. Hall, Richard Sallari, Javed Khan, Berkley E. Gryder, Isaac Brownell
Lingling Miao, David Milewski, Amy Coxon, Tara Gelb, Khalid A. Garman, Jadon Porch, Arushi Khanna, Loren Collado, Natasha T. Hill, Kenneth Daily, Serena Vilasi, Danielle Reed, Tiffany Alexander, Gabriel J. Starrett, Maharshi Chakraborty, Young Song, Rachel Choi, Vineela Gangalapudi, Josiah Seaman, Andrew Morton, Klaus J. Busam, Christopher R. Vakoc, Daniel J. Urban, Min Shen, Matthew D. Hall, Richard Sallari, Javed Khan, Berkley E. Gryder, Isaac Brownell
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Research Article Dermatology Oncology

Interlocking host and viral cis-regulatory networks drive Merkel cell carcinoma

Abstract

Over 15% of cancers worldwide are caused by viruses. Merkel cell polyomavirus (MCPyV) is the most recently discovered human oncovirus and is the only polyomavirus that drives malignant tumors in humans. Here, we show that MCPyV+ Merkel cell carcinoma is defined by neuroendocrine-lineage core regulatory (CR) transcription factors (TFs) (ATOH1, INSM1, ISL1, LHX3, POU4F3, and SOX2) that were essential for tumor survival and that co-bound chromatin with the viral small T antigen at super enhancers. Moreover, MCPyV integration sites were enriched at these neuroendocrine super enhancers. We further discovered that the MCPyV noncoding control region contained a homeodomain binding motif absent in other polyomaviruses that bound ISL1 and LHX3 and depended on them for T antigen expression. To therapeutically target the CR factors, we used histone deacetylase (HDAC) inhibitors to collapse the chromatin architecture and induce topological blurring of superenhancer loops, abrogating core TF expression and halting tumor growth. To our knowledge, our study presents the first example of oncogenic cross-regulation between viral and human epigenomic circuitry to generate interlocking and essential transcriptional feedback circuits that explain why MCPyV causes neuroendocrine cancer and represent a tumor dependency that can be targeted therapeutically.

Authors

Lingling Miao, David Milewski, Amy Coxon, Tara Gelb, Khalid A. Garman, Jadon Porch, Arushi Khanna, Loren Collado, Natasha T. Hill, Kenneth Daily, Serena Vilasi, Danielle Reed, Tiffany Alexander, Gabriel J. Starrett, Maharshi Chakraborty, Young Song, Rachel Choi, Vineela Gangalapudi, Josiah Seaman, Andrew Morton, Klaus J. Busam, Christopher R. Vakoc, Daniel J. Urban, Min Shen, Matthew D. Hall, Richard Sallari, Javed Khan, Berkley E. Gryder, Isaac Brownell

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Figure 3

VP-MCC SEs are associated with MCPyV integration sites.

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VP-MCC SEs are associated with MCPyV integration sites. (A) MCPyV integr...
(A) MCPyV integration sites (red) overlaid with SE sites that are recurrent among the 4 VP-MCC cell lines (sea blue). The clonal integration coordinates (unique for each VP-MCC tumor) are indicated in the center, and a 2 Mb window is shown around each. H3K27ac HiChIP from MKL-1 cells is shown above, with topological domain boundaries outlined in blue. (B) Histogram of the distances between MCPyV integration sites (n = 90 tumors) to the nearest VP-MCC SE, compared with SEs in other cell types, random genomic locations, and VN-MCC SEs. (C) Absolute distance between MCPyV integration sites and VP-MCC SEs, or to SEs from other human cell types and tissues, or to the nearest random genomic location, or to VN-MCC SEs. P values were determined using a Wilcoxon matched-pairs rank test. Data are summarized by box (quartiles) and whisker (1.5 × IQR) plots, with the median (thick center line). (D) Illustration of increased chromatin accessibility at SEs correlating with viral integration sites. (E) Percentage of integration sites by chromatin compartments defined by H3K27ac HiChIP data in MKL-1 cells. A compartment = euchromatin; B compartment = heterochromatin. (F) Heatmap of the human chromatin accessibility atlas (22) overlapped with VP-MCC SEs and MCPyV integration sites.