The broad reach of the effect of mutations in the complex, called BAF, rivals that of another well-known tumor suppressor called p53. It also furthers a growing notion that these so-called chromatin-regulatory complexes may function as much more than mere cellular housekeepers.
"Although we knew that this complex was likely to play a role in preventing cancer, we didn't realize how extensive it would be," said postdoctoral scholar Cigall Kadoch, PhD. "It's often been thought that these complexes play supportive, maintenance-like roles in the cell. But this is really changing now."
Kadoch shares lead authorship of the study with postdoctoral scholar Diana Hargreaves, PhD. Gerald Crabtree, MD, professor of developmental biology and of pathology, is the senior author of the study, which will be published online May 5 in Nature Genetics.
Chromatin-regulatory complexes work to keep DNA tightly condensed, while also granting temporary access to certain portions for replication or to allow the expression of genes necessary for the growth or function of the cell.
Members of Crabtree's laboratory have been interested in BAF complexes and their function for many years. Recently, they reported in the journal Nature that switching subunits within these complexes can convert human fibroblasts to neurons, which points to their instructive role in development and, possibly, cancer.
"Somehow these chromatin-regulatory complexes manage to compress nearly two yards of DNA into a nucleus about one one-thousandth the size of a pinhead," said Crabtree, who is also a member of the Stanford Cancer Institute and a Howard Hughes Medical Institute investigator. "And they do this without compromising the ability of the DNA to be replicated and selectively expressed in different tissues - all without tangling. In 1994 we reported that complexes of this type were likely to be tumor suppressors. Here we show that they are mutated in nearly 20 percent of all human malignancies thus far examined."
The researchers combined biochemical experiments with the data mining of 44 pre-existing studies to come to their conclusions, which would not have been possible without the advent of highly accurate, genome-wide DNA sequencing of individual human tumor samples. Interestingly, mutations to certain subunits, or particular combinations of mutations in the complex's many subunits, seem to herald the development of specific types of cancer - favoring the development of ovarian versus colon cancer, for example.
The importance of the BAF complex as a tumor suppressor is further emphasized by the fact that, in some cases, a mutation in one subunit is sufficient to initiate cancer development.
"For example," said Kadoch, "a type of mutation called a chromosomal translocation in the gene encoding one of these newly identified subunits, SS18, is known to be the hallmark of a cancer called synovial sarcoma. It is clearly the driving oncogenic event and very often the sole genomic abnormality in these cancers." Kadoch and Crabtree published a study in March in Cell uncovering the mechanism and functional consequences of BAF complex perturbation in synovial sarcoma.
The startling prevalence of mutations in the BAF complex was discovered when Kadoch conducted a series of experiments to determine exactly which proteins in the cell were true subunits of the complex. (The exact protein composition of the large complex varies among cell types and species.) Kadoch used an antibody that recognized one core component to purify intact BAF complexes in various cell types, including embryonic stem cells and skin, nerve and other cells. She then analyzed the various proteins isolated by the technique.
Using this method, Kadoch identified seven proteins previously unknown to be BAF components. She and Hargreaves then turned to previously published studies in which the DNA from a variety of human tumors had been sequenced to determine how frequently any of the members of the complex were mutated.
The results, once the newly discovered members were included, were surprising: 19.6 percent of all human tumors displayed a mutation in at least one of the complex's subunits. In addition, for some types of cancers (such as synovial sarcoma), every individual tumor sample examined had a mutation in a BAF subunit. The results suggest that the BAF complex, when unmutated, plays an important protective role against the development of cancer in many different tissues.
The researchers are now focused on learning how the mutations affect the tumor-suppressing activity of the BAF complex.
"We certainly want to further our understanding of the mechanism behind these findings," said Hargreaves. "Do they promote cancer development by inhibiting the proper progression of the cell cycle? Or perhaps they affect how the complex is positioned on the DNA. We'd like to determine how to recapitulate some of these mutations experimentally to see what types of defects they introduce into the complex."
Other Stanford authors of the study include postdoctoral scholar Courtney Hodges, PhD, and former lab members Laura Elias, PhD, and Lena Ho, PhD.
The research was funded by the National Institutes of Health (grants NS046789, CA163915 and F32HD072627), the National Science Foundation, the Howard Hughes Medical Institute and the Helen Hay Whitney Foundation.
Information about Stanford's Department of Developmental Biology and Department of Pathology, which also supported the work, is available at http://devbio.stanford.edu and http://pathology.stanford.edu.The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.
Krista Conger | EurekAlert!
Enduring cold temperatures alters fat cell epigenetics
19.04.2018 | University of Tokyo
Full of hot air and proud of it
18.04.2018 | University of Pittsburgh
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...
In an article that appears in the journal “Review of Modern Physics”, researchers at the Laboratory for Attosecond Physics (LAP) assess the current state of the field of ultrafast physics and consider its implications for future technologies.
Physicists can now control light in both time and space with hitherto unimagined precision. This is particularly true for the ability to generate ultrashort...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
19.04.2018 | Materials Sciences
19.04.2018 | Physics and Astronomy
19.04.2018 | Physics and Astronomy