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3D Chromosomal Architecture and Nuclear Topology

May 2–5, 2019

Chaired By

 Ari Melnick, MD of Cornell Medical College
 Jane Skok, PhD of New York University

Meeting Description

The precise and detailed 3D organization of chromosomal and chromatin looping is just now being understood to play a fundamental role in regulation of gene expression, DNA repair, DNA replication and cell cycle. Disruption of nuclear topology is a emerging as a potential new hallmark of cancer. For example somatic mutation of the loop and boundary protein CTCF are prevalent in many types of cancer, as are mutations of the various proteins that make up or regulate the cohesin complex that plays a central role in architectural effects. In addition there is rapidly increasing body of evidence that somatic mutation of looping elements can drive development of cancerby either disrupting the location of large gene enhancer clusters, boundary elements, lncRNAs that strengthen looping, and binding affinity of regulatory DNA elements for proteins that drive specific 3D architectural features.

Moreover it seems like master regulatory transcription factors may mark sites for preferential redistribution of 3D anchor points of various kinds. There are many new and fascinating observations coming out, novel mouse models, patient based observations. There is tremendous excitement currently about this new frontier in biology and its relation to cancer. I have chaired special lecture sessions on this for example at the AACR annual meeting and other venues. A conference on this new and very hot topic would be very impactful in disseminating ideas and creating new avenues of attack for understanding how nuclear topology drives normal and malignant biology, and perhaps generating some ideas on how the study of this novel field could lead to biomarkers and therapies for cancer patients.

Meeting Summary

The symposium brought together basic mechanism of nuclear architecture from the computational and mechanistic perspective with studies of cancer genetics and cancer biology. The rationale for this symposium was related to the fact that we are starting to understand that the ability of cells to control the three dimensional architecture of their genomes plays a fundamental and essential role in coordinating and controlling gene expression and thus creating all the various cellular phenotypes in the human body. Along these lines there are nascent data showing that mutations affecting either the proteins that mediate genomic architecture, or the non-coding genomic elements to which they bind are extremely common in human cancers. Moreover, emerging data show that the types of mutations that occur in cancer may be determined by the position of genes within cell nuclei. Hence it was critical to bring together experts in nuclear architecture with cancer biologists and physicians to see how this information can be merged to together to understand and eventually target this fundamental property of cancer cells.

The goals of this meeting where to:

  • To discuss new ideas, unpublished data and ask provocative questions directed towards stimulating creative and impactful science
  • To link fundamental concepts in nuclear topology and epigenetics with notions of cancer biology and tumor immunity
  • To generate new scientific collaborations that deploy novel concepts and apply cutting edge research towards understanding and defeating cancer
  • To create a safe and trusting environment where participants feel comfortable sharing novel findings and openly discussing important new concepts they are developing
  • To provide mentorship, guidance and inspiration to junior scientists participating in the meeting

The participants were asked to address the following questions:

  1. Is disruption of nuclear architecture a fundamental property of cancer?
  2. Does aberrant nuclear architecture drive the cancer phenotype?
  3. Are there any druggable targets among proteins that control or regulate chromosome architecture?
  4. What are the definitions of TADs and compartments in cancer?
  5. Is the cancer phenotype limited to disruption of intra-TAD epigenetic effects?
  6. Can architectural elements drive cancer phenotypes?
  7. How do mutations in cohesins and CTCF cause cancer?
  8. Can somatic mutations in non-coding DNA function as cancer drivers?
  9. Can alterations in chromatin modifiers in cancer enable greater understanding of the functional interplay between chromatin and 3D architecture.
  10. Is topological conformation an epigenetic mark?
  11. How is the concept of nuclear topology linked to the notion of phase separation?

These and other points were discussed vigorously and lead to some of the following considerations:

Cancer relevance of topology mechanisms could not be stronger. Some of these considerations include the i) frequent mutations in topological mediator genes, ii) mutations in elements that control topological domains, iii) disruption of mechanisms that regulate gene expression through formation of biochemical condensates that likely include gene regulatory elements, and iv) extensive evidence for deregulated architecture coming from tumor model systems and primary human patient specimens. One aspect that came into focus is the lack of consensus and clear data to indicate the precise nature of architectural features. Part of this is due to the complexity of translating abstract representations into physical features such as loops, etc. There is also semantic confusion, and variable interpretation due to different analysis algorithms and interpretation. The approaches for studying nuclear topology are highly complicated and involve very advanced technologies and expensive equipment and sequencing.

When novel basic concepts translate into the more translational cancer field there can be a “broken telephone effect” and hopefully the experience of this meeting will inform precision of language to empower the cancer field to articulate the most significant hypotheses.

The lively and informative discussion helped tremendously to move the ball forward on all fronts and trigger many new ideas and projects. Every discussion section was inspirational and riveting.

A few examples of important insights gained from the data and collective brainstorming include:

  • The motor function for Cohesin is a game changer and provides a terrific basis upon which to interpret the impact of cohesin complex mutations and structural effects in cancer. There is still a disconnect between basic cohesin biochemistry and cancer mechanism that needs to be bridged.
  • Topological interpretation of cancer genetics is potentially transformative. Using approaches that integrate genome structure, chromosomal topology and the epigenome – will allow us to define the regulatory and biological state of cancer cells much more accurately.
  • One area emerging as a high priority for cancer research is the consideration of how structural changes in the genome such as chromothrypsis, CNVs, aberrant chromosomal structures and transposons and ERV disposition can reprogram the epigenome to influence cancer cell biology.
  • Also of critical importance is the finding that activation of transposons and non-coding elements can dynamically change genomic architecture in cancer by providing binding sites for architectural proteins in the wrong places, thus reprogramming normal cells to behave as malignant ones.
  • New approaches for imaging of chromatin are emerging that allow direct measurement and observation of chromatin domains and biochemical condensates including in living cells, and as a result of this meeting will applied to cancer research studies in humans and experimental animal models.
  • The role of CTCF in determining the regulatory architectural structure of the genome in normal and cancer cells remains difficult to pin down, even though gain and loss of function experiments show that cancers alter its boundary functions leading to significant changes in gene expression and biological potential.

Critical contributions were made by the three Forbeck Scholars who were invited to participate in the meeting:

  • Danfeng Cai, from the NIH
  • Peter Ly, from UT Southwestern
  • Kathleen Xie, from Harvard
This was an exceptional group of young investigators who participated actively and made important contributions to the discussion.

Some of the immediate outcomes of this meeting are:

  • An expanded directive to sequence non-coding DNA elements in cancer patients, which will be actively pursued by several of the participants who perform cancer profiling studies.
  • The application of novel technologies to visualize genomic architecture in cancer patients to primary patient specimens for the better identification of cancer causing mutations.
  • The integration of novel and unpublished findings on architectural protein mechanism of action with cancer models – providing new insight into how tumors work.
  • A major novel concept that arose through discussion was that of identifying therapeutic agents that could reverse aberrant nuclear topology in cancer – by bringing together technologies and discoveries from different laboratories. Several participants announced plans to use these technologies to screen for such therapies.
  • The co-organizers of this meeting had not previously collaborated scientifically but through their interactions on setting up the meeting submitted and obtained the first National Cancer Institute Program Project Grant on Nuclear Topology in Cancer. Several of the participants in the Forbeck Symposium agreed to serve on the external advisory board of this PPG, thus providing a forum for ongoing discussion and collaboration on this topic.
  • Judging from the many vibrant discussions and group breakout discussions we expect that many additional collaborative projects are being launched.

Forum Participants

Eftychia Apostolou, PhD
Weill Cornell Medicine

Gerd A. Blobel, MD, PhD
University of Pennsylvania Pearlman School of Medicine

Danfeng Cai, PhD
National Institutes of Health
 Forbeck Scholar

Wouter De Laat, PhD
Hubrecht Institute

Peter Fraser, PhD
Florida State University

Susana Hadjur
University College London

Ross Levine, MD
Memorial Sloan Kettering Cancer Center

Mathieu Lupien, PhD
University of Toronto

Peter Ly, PhD
UT Southwestern
 Forbeck Scholar

Ari Melnick, MD
Cornell University

Leonid Mirny, PhD, MSc
Massachusetts Institute of Technology

Kim Nasmyth, PhD
Trinity College of Oxford University

Clodagh O'Shea, PhD
Salk Institute for Biological Studies

Tomi Pastan, MD, PhD
University of Missouri-Kansas City

Jan-Michael Peters
Research Institute of Molecular Pathology

Jennifer E. Phillips-Cremins, PhD
University of Pennsylvania

Ana Pombo
Max Delbruch Center for Molecular Medicine

Bing Ren, PhD
Ludwig Cancer Research

Benjamin Rowland
Netherlands Cancer Institute

Peter Scacheri, PhD
Case Western Reserve University

Jane Skok, PhD
NYU Langone Health

Francois Spitz
Pasteur Institute

Kathleen T. Xie, PhD
Dana-Farber Cancer Institute
 Forbeck Scholar