Monday, December 15th, 2014

Time	Event
10:30a	Proteins drive cancer cells to change states A new study from MIT implicates a family of RNA-binding proteins in the regulation of cancer, particularly in a subtype of breast cancer. These proteins, known as Musashi proteins, can force cells into a state associated with increased proliferation. Biologists have previously found that this kind of transformation, which often occurs in cancer cells as well as during embryonic development, is controlled by transcription factors — proteins that turn genes on and off. However, the new MIT research reveals that RNA-binding proteins also play an important role. Human cells have about 500 different RNA-binding proteins, which influence gene expression by regulating messenger RNA, the molecule that carries DNA’s instructions to the rest of the cell. “Recent discoveries show that there’s a lot of RNA-processing that happens in human cells and mammalian cells in general,” says Yarden Katz, a recent MIT PhD recipient and one of the lead authors of the new paper. “RNA is processed at several points within the cell, and this gives opportunities for RNA-binding proteins to regulate RNA at each point. We’re very interested in trying to understand this unexplored class of RNA-binding proteins and how they regulate cell-state transitions.” Feifei Li of China Agricultural University is also a lead author of the paper, which appears in the journal eLife on Dec. 15. Senior authors of the paper are MIT biology professors Christopher Burge and Rudolf Jaenisch, and Zhengquan Yu of China Agricultural University. Controlling cell states Until this study, scientists knew very little about the functions of Musashi proteins. These RNA-binding proteins have traditionally been used to identify neural stem cells, in which they are very abundant. They have also been found in tumors, including in glioblastoma, a very aggressive form of brain cancer. “Normally they’re marking stem and progenitor cells, but they get turned on in cancers. That was intriguing to us because it suggested they might impose a more undifferentiated state on cancer cells,” Katz says. To study this possibility, Katz manipulated the levels of Musashi proteins in neural stem cells and measured the effects on other genes. He found that genes affected by Musashi proteins were related to the epithelial-to-mesenchymal transition (EMT), a process by which cells lose their ability to stick together and begin invading other tissues. EMT has been shown to be important in breast cancer, prompting the team to look into Musashi proteins in cancers of non-neural tissue. They found that Musashi proteins are most highly expressed in a type of breast tumors called luminal B tumors, which are not metastatic but are aggressive and fast-growing. When the researchers knocked down Musashi proteins in breast cancer cells grown in the lab, the cells were forced out of the epithelial state. Also, if the proteins were artificially boosted in mesenchymal cells, the cells transitioned to an epithelial state. This suggests that Musashi proteins are responsible for maintaining cancer cells in a proliferative, epithelial state. “These proteins seem to really be regulating this cell-state transition, which we know from other studies is very important, especially in breast cancer,” Katz says. Embryonic development and cancer The researchers found that Musashi proteins repress a gene called Jagged1, which in turn regulates the Notch signaling pathway. Notch signaling promotes cell division in neurons during embryonic development and also plays a major role in cancer. When Jagged1 is repressed, cells are locked in an epithelial state and are much less motile. The researchers found that Musashi proteins also repress Jagged1 during normal mammary-gland development, not just in cancer. When these proteins were overexpressed in normal mammary glands, cells were less able to undergo the type of healthy EMT required for mammary tissue development. Brenton Graveley, a professor of genetics and developmental biology at the University of Connecticut, says he was surprised to see how much influence Musashi proteins can have by controlling a relatively small number of genes in a cell. “Musashi proteins have been known to be interesting for many years, but until now nobody has really figured out exactly what they’re doing, especially on a genome-wide scale,” he says. The researchers are now trying to figure out how Musashi proteins, which are normally turned off after embryonic development, get turned back on in cancer cells. “We’ve studied what this protein does, but we know very little about how it’s regulated,” Katz says. He says it is too early to know if the Musashi proteins might make good targets for cancer drugs, but they could make a good diagnostic marker for what state a cancer cell is in. “It’s more about understanding the cell states of cancer at this stage, and diagnosing them, rather than treating them,” he says. The research was funded by the National Institutes of Health. (Comment on this)
10:59a	New findings could point the way to “valleytronics” New findings from a team at MIT and other institutions could provide a pathway toward a kind of two-dimensional microchip that would make use of a characteristic of electrons other than their electrical charge, as in conventional electronics. The new approach is dubbed “valleytronics,” because it makes use of properties of an electron that can be depicted as a pair of deep valleys on a graph of their traits. The findings are described in a paper appearing in the journal Nature Materials, co-authored by MIT graduate student Edbert Jarvis Sie, MIT associate professor Nuh Gedik, and five others. The material the team studied is called tungsten disulfide (WS2), which belongs to a class of 2-D crystals known as transition metal dichalcogenides (TMDs). Like the single-layer carbon material called graphene, TMDs form thin films with a hexagonal, chicken-wire-like structure just a few atoms in thickness. (In the case of graphene, it is just a single atomic layer, while the TMDs are three atoms thick.) Conventional electronics, including the microchips that power today’s computers, smartphones and tablets, manipulate charges carried by the electrons that flow through them. But other characteristics of the electrons could also be used to carry information: Their spin, for example, could lead to new “spintronic” devices. Now valleytronics, another way of storing and manipulating data, could take a step toward practical applications through this latest research. Valleytronics, which is a bit less intuitive to understand, has the potential to produce highly efficient devices, the team says. It is based on the fact that in certain materials, when the energy of electrons is plotted relative to their momentum on a graph, the resulting curve features two deep valleys. If subjected to certain perturbations, these two valleys can have unequal depth, giving the electrons a preference to populate one of the two valleys. The two different states can be used to represent the zeroes and ones of data. “We discovered a way to directly control this valley by using light,” explains Sie, a PhD student in physics. And because of the two-dimensional nature of the material and its mechanical strength, valleytronics could be used to make flexible electronics, adds Gedik, the Biedenharn Career Development Associate Professor of Physics. While tungsten disulfide could be used to create conventional charge-based electronic devices, or spintronic devices, it also has the properties needed, in theory, to create valleytronics, Gedik says. On the chart of the energy of electrons in this material versus their momentum, “an electron cannot take any value it wants, it has to be on a specific curve, and that curve has two valleys,” he explains. Electrons naturally settle into the lowest-energy values available, but in this material that low point can be in either of the two valleys, since the electrons in the two valleys have equal energy. However, it is desirable to induce a difference in the energies of the electrons in the two valleys, since that difference can then be used to transfer information, Gedik says. This much was already known, but attempts to shift the relative energies of the valleys have been limited to the idea of using magnetic fields. The problem is that the strength of the magnetic fields needed to achieve even a minuscule change in the valleys is far greater than can be achieved in an ordinary lab — hundreds of tesla. The significant advance reported in this new research is that a much greater energy shift can be achieved with a relatively conventional laser pulse with a special polarization, providing a new method of control for valleytronic devices, the researchers say. In principle, Gedik says, it should now be possible to design devices in which all three properties of the electrons — charge, spin, and valleys — could be independently manipulated. This work is just a beginning, Gedik says. Knowing that the effect works well in this material, the team hypothesized that it should also be possible to induce a new state of matter in this material using the same approach. “We want to actually experimentally observe this, and show that this new state exists,” he says. David Hsieh, an assistant professor of physics at Caltech who was not connected to this research, says, “Being able to manipulate the valley degree of freedom in two-dimensional transition metal dichalcogenides would enable their application in the field of valleytronics. … This experiment makes a large step toward realizing this goal by demonstrating a method to control the energy difference between two valleys in tungsten disulfide for the first time.” The research team also included MIT assistant professor of physics Liang Fu and associate professor of electrical engineering Jing Kong, graduate student James McIver of MIT and Harvard University, and assistant professor Yi-Hsien Lee of National Tsing-Hua University in Taiwan. The work was supported by the Department of Energy, the National Science Foundation, and the Ministry of Science and Technology of the Republic of China. (Comment on this)

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