ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas

  1. Hanseul Yang
  2. Daniel Schramek
  3. Rene C Adam
  4. Brice E Keyes
  5. Ping Wang
  6. Deyou Zheng
  7. Elaine Fuchs  Is a corresponding author
  1. Howard Hughes Medical Institute, The Rockefeller University, United States
  2. Mount Sinai Hospital, United States
  3. Albert Einstein College of Medicine, United States

Abstract

Tumor-initiating stem cells (SCs) exhibit distinct patterns of transcription factors and gene expression compared to healthy counterparts. Here, we show that dramatic shifts in large open-chromatin domain (super-enhancer) landscapes underlie these differences and reflect tumor microenvironment. By in vivo super-enhancer and transcriptional profiling, we uncover a dynamic cancer-specific epigenetic network selectively enriched for binding motifs of a transcription factor cohort expressed in squamous cell carcinoma SCs (SCC-SCs). Many of their genes, including Ets2 and Elk3, are themselves regulated by SCC-SC super-enhancers suggesting a cooperative feed-forward loop. Malignant progression requires these genes, whose knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCCs. ETS2-deficiency disrupts the SCC-SC super-enhancer landscape and downstream cancer genes while ETS2-overactivation in epidermal-SCs induces hyperproliferation and SCC super-enhancer-associated genes Fos, Junb and Klf5. Together, our findings unearth an essential regulatory network required for the SCC-SC chromatin landscape and unveil its importance in malignant progression.

Article and author information

Author details

  1. Hanseul Yang

    Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  2. Daniel Schramek

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, United States
    Competing interests
    No competing interests declared.
  3. Rene C Adam

    Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  4. Brice E Keyes

    Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  5. Ping Wang

    Department of Neurology, Albert Einstein College of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  6. Deyou Zheng

    Department of Neurology, Albert Einstein College of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  7. Elaine Fuchs

    Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    For correspondence
    elaine.fuchs@rockefeller.edu
    Competing interests
    Elaine Fuchs, Reviewing editor, eLife.

Ethics

Animal experimentation: Mice were maintained in the Association for Assessment and Accreditation of Laboratory Animal Care-accredited animal facility of The Rockefeller University (RU), and procedures were performed with Institutional Animal Care and Use Committee (IACUC)-approved protocols (#13622-H, #14693-H and #14765-H).

Human subjects: Tissue microarrays comprising healthy human skin samples, human skin SCCs as well as head and neck SCCs (HNSCC) were obtained from US Biomax, Rockeville. All tissue is collected under the highest ethical standards with the donor being informed completely and with their consent. The company followed standard medical care and protect the donors' privacy. All human tissues are collected under HIPPA approved protocols.

Copyright

© 2015, Yang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 4,909
    views
  • 1,226
    downloads
  • 71
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Hanseul Yang
  2. Daniel Schramek
  3. Rene C Adam
  4. Brice E Keyes
  5. Ping Wang
  6. Deyou Zheng
  7. Elaine Fuchs
(2015)
ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas
eLife 4:e10870.
https://doi.org/10.7554/eLife.10870

Share this article

https://doi.org/10.7554/eLife.10870

Further reading

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine
    Joshua G Medina-Feliciano, Griselle Valentín-Tirado ... José E Garcia-Arraras
    Research Article

    In holothurians, the regenerative process following evisceration involves the development of a ‘rudiment’ or ‘anlage’ at the injured end of the mesentery. This regenerating anlage plays a pivotal role in the formation of a new intestine. Despite its significance, our understanding of the molecular characteristics inherent to the constituent cells of this structure has remained limited. To address this gap, we employed state-of-the-art scRNA-seq and hybridization chain reaction fluorescent in situ hybridization analyses to discern the distinct cellular populations associated with the regeneration anlage. Through this approach, we successfully identified 13 distinct cell clusters. Among these, two clusters exhibit characteristics consistent with putative mesenchymal cells, while another four show features akin to coelomocyte cell populations. The remaining seven cell clusters collectively form a large group encompassing the coelomic epithelium of the regenerating anlage and mesentery. Within this large group of clusters, we recognized previously documented cell populations such as muscle precursors, neuroepithelial cells, and actively proliferating cells. Strikingly, our analysis provides data for identifying at least four other cellular populations that we define as the precursor cells of the growing anlage. Consequently, our findings strengthen the hypothesis that the coelomic epithelium of the anlage is a pluripotent tissue that gives rise to diverse cell types of the regenerating intestinal organ. Moreover, our results provide the initial view into the transcriptomic analysis of cell populations responsible for the amazing regenerative capabilities of echinoderms.

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine
    Joseph A Bisson, Miriam Gordillo ... Todd Evans
    Research Article

    Haploinsufficiency for GATA6 is associated with congenital heart disease (CHD) with variable comorbidity of pancreatic or diaphragm defects, although the etiology of disease is not well understood. Here, we used cardiac directed differentiation from human embryonic stem cells (hESCs) as a platform to study GATA6 function during early cardiogenesis. GATA6 loss-of-function hESCs had a profound impairment in cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation due to early defects during the mesendoderm and lateral mesoderm patterning stages. Profiling by RNA-seq and CUT&RUN identified genes of the WNT and BMP programs regulated by GATA6 during early mesoderm patterning. Furthermore, interactome analysis detected GATA6 binding with developmental transcription factors and chromatin remodelers, suggesting cooperative regulation of cardiac lineage gene accessibility. We show that modulating WNT and BMP inputs during the first 48 hr of cardiac differentiation is sufficient to partially rescue CPC and CM defects in GATA6 heterozygous and homozygous mutant hESCs. This study provides evidence of the regulatory functions for GATA6 directing human precardiac mesoderm patterning during the earliest stages of cardiogenesis to further our understanding of haploinsufficiency causing CHD and the co-occurrence of cardiac and other organ defects caused by human GATA6 mutations.