Cancer: A mutation that breaks gene interplay in 3D

January 28, 2019

Inside the cell, DNA is tightly wrapped around proteins and packed in a complex, 3D structure that we call "chromatin". Chromatin not only protects our genetic material from damage, but also organizes the entire genome by regulating the expression of genes in three dimensions, unwinding them to be presented to the cell's gene-expression machinery and then winding them back in.

Inside the 3D chromatin structure there are certain regions called "topologically associating domains" or TADs. These contain DNA sequences (thousands to millions of DNA bases) that physically interact with each other, suggesting that the genes in these domains may be working together. Discovered in 2012, the functions of TADs are not yet fully understood, but it is known that disrupting TADs disrupts gene regulation, and this can be a mechanism that cancer cells use to alter gene expression.

Now, scientists led by Elisa Oricchio at EPFL, in collaboration with Giovanni Ciriello at UNIL, have discovered that a mutation of a particular gene leads to modifying interactions within TADs. The gene is called EZH2 and is normally involved in the repression of gene transcription - the first step in gene expression. In fact, EZH2 mutations play key roles in the initiation of tumors and can be used as marker for diagnosing several different types of cancers.

The scientists studied what is known as a gain-of-function mutation of EZH2. These types of mutations exacerbate the gene's function and help tumor cells to grow. Here, the researchers found that EZH2 does not act randomly across the genome but rather preferentially within specific TADs.

Mutated EZH2 shuts down entire domains, turning off genes that normally suppress tumors. In their study, the loss of multiple genes synergistically accelerated the development of the tumors. And when the researchers inhibited mutated EZH2 with a drug, all the functions were restored.

The study is the first to show that mutated EZH2 affects not individual genes but entire chromatin domains, changing the interactions and expression of tumor-suppressive genes contained in those domains.

"The study highlights the importance of considering the 3D organization of the genome in the nucleus to better understand how mutations in cancer cells exploit this organization to support tumor growth," says Elisa Oricchio. "Pharmacological inhibitors that block EZH2 oncogenic activity are currently in clinical trials, and this study provides further insight on their therapeutic potential."
-end-
Professor Oricchio's lab is part of the Swiss Institute for Experimental Cancer Research (ISREC) within the School of Life Sciences at EPFL. ISREC is deeply involved in the Swiss Cancer Center Léman (SCCL), a cancer research consortium that includes the University hospital of Lausanne (CHUV), the Geneva University Hospitals (HUG), the universities of Lausanne (UNIL) and Geneva (UNIGE), and EPFL.

Other contributors

University of Lausanne (UNIL)
Swiss Institute of Bioinformatics (SIB)
EPFL Institute of Physics

Reference

Maria C. Donaldson-Collier, Stephanie Sungalee, Marie Zufferey, Daniele Tavernari, Natalya Katanayeva, Elena Battistello, Marco Mina, Kyle M. Douglass, Timo Rey, Franck Raynaud, Suliana Manley, Giovanni Ciriello, Elisa Oricchio. EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains. Nature Genetics 28 January 2019. DOI: 10.1038/s41588-018-0338-y

Ecole Polytechnique Fédérale de Lausanne

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.