The study, published in Nature Communications, helps to clarify a potential therapeutic strategy and adds to the knowledge of ASXL1 gene expression.

Epigenetics refers to chemical modifications of a cell’s genetic material that control how genes are expressed and affect the interpretation of the DNA code. Research shows epigenetics play a critical role in the development and progression of many diseases, including cancer.

“The epigenome in patients with these ASXL1 gene mutations is changed in a way that allows the cancer cells to switch on genes that are detrimental to the patients,” says Moritz Binder M.D., a Mayo Clinic hematologist and scientist, and the lead author of the study. Dr. Binder is a 2021 Gerstner Family Career Development awardee.

“These epigenetic changes don’t affect the DNA blueprint itself,” Dr. Binder explains. “It affects how to the blueprint is read — which pages to read and which pages not to read.”

Chronic myelomonocytic leukemia is a cancer that typically affects people 60 and older. It starts in blood-forming cells of the bone marrow and invades the blood. Nearly 40% of patients with chronic myelomonocytic leukemia have a mutation in the ASXL1 gene.

“Unfortunately, patients with ASXL1 mutations do not fare well and do not respond as well to the treatments currently available,” Dr. Binder says.

For the study, Dr. Binder and his team conducted a comprehensive multi-omics interrogation using a variety of high-throughput sequencing methods. Multi-omics offers the opportunity to understand the flow of information that underlies disease.

The researchers compared samples from patients with and without ASXL1 mutations and analyzed the activity of genes along with molecules around the DNA. The investigation included gene expression and several modifications affecting the packaging of the DNA.

“This allowed us to perform modeling to draw inference about the effect of epigenetic changes in isolation and in concert on leukemogenic gene expression in ASXL1-mutant chronic myelomonocytic leukemia,” Dr. Binder says.

Overall, they found that ASXL1 mutations are associated with the overexpression of key genes that drive leukemia.

“Our study supports the notion that several important leukemogenic driver genes are under the control of regulatory elements in the genome,” Dr. Binder says.

The data suggest that these regulatory elements are only functional in patients with ASXL1-mutant chronic myelomonocytic leukemia and may therefore represent new individualized therapeutic targets. Dr. Binder is planning to translate these findings into early phase clinical trials soon.

“Our study is the basis for ongoing work to further explore ways to target these patient-specific regulatory elements with novel small-molecule drugs, “Dr. Binder says. “With this approach, we hope to restore normal gene expression, or at least treat the cancer cells in a new way to overcome the detrimental effect of ASXL1 mutations.”

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Materials provided by Mayo Clinic. Original written by Susan Murphy. Note: Content may be edited for style and length.

The underlying physics driving these switchable materials is a mystery, though physicists suspect it has something to do with “electron correlations,” or effects from the interaction felt between two negatively charged electrons. These particle repulsions have little to no effect in shaping the properties in most materials. But in two-dimensional materials, these quantum interactions can be a dominating influence. Understanding how electron correlations drive electrical states can help scientists engineer exotic functional materials, such as unconventional superconductors.

Now, physicists at MIT and elsewhere have taken a significant step toward understanding electron correlations. In a paper appearing today in Science, the researchers reveal direct evidence of electron correlations in a two-dimensional material called ABC trilayer graphene. This material has previously been shown to switch from a metal to an insulator to a superconductor.

For the first time, the researchers directly detected electron correlations in a special insulating state of the material. They also quantified the energy scales of these correlations, or the strength of the interactions between electrons. The results demonstrate that ABC trilayer graphene can be an ideal platform to explore and possibly engineer other electron correlations, such as those that drive superconductivity.

“Better understanding of the underlying physics of superconductivity will allow us to engineer devices that could change our world, from zero-loss energy transmission to magnetically levitating trains,” says lead author Long Ju, assistant professor of physics at MIT. “This material is now a very rich playground to explore electron correlations and build even more robust phenomena and devices.”

Superlattice

An ABC trilayer graphene, stacked atop a layer of hexagonal boron nitride, is similar to the more well-studied magic-angle bilayer graphene, in that both materials involve layers of graphene — a material that is found naturally in graphite and can exhibit exceptional properties when isolated in its pure form. Graphene is made from a lattice of carbon atoms arranged in a hexagonal pattern, similar to chicken wire. Hexagonal boron nitride, or hBN, has a similar, slightly larger hexagonal pattern.

In ABC trilayer graphene, three graphene sheets are stacked at the same angle and slightly offset from each other, like layered slices of cheese. When ABC trilayer graphene sits on hBN at a zero-degree twist angle, the resulting structure is a moiré pattern, or “superlattice,” made up of periodic energy wells, the configuration of which determines how electrons flow through the material.

“This lattice structure forces electrons to localize, and sets the stage for electron correlations to have a huge impact on the material’s macroscopic property,” Ju says.

He and his colleagues sought to probe ABC trilayer graphene for direct evidence of electron correlations and to measure their strength. They first synthesized a sample of the material, creating a superlattice with energy wells, each of which can normally hold two electrons. They applied just enough voltage to fill each well in the lattice.

Electron boost

They then looked for signs that the material was in an ideal state for electron correlations to dominate and affect the material’s properties. They specifically looked for signs of a “flat band” structure, where all electrons have almost the same energy. The team reasoned that an environment hosting electrons with a wide range of energies would be too noisy for the tiny energy of electron correlations to have an effect. A flatter, quieter environment would allow for these effects to come through.

The team used a unique optical technique they developed to confirm that the material indeed has a flat band. They then tuned down the voltage slightly, so that only one electron occupied each well in the lattice. In this “half-filled” state, the material is considered a Mott insulator — a curious electrical state that should be able to conduct electricity like metal, but instead, due to electron correlations, the material behaves as an insulator.

Ju and his colleagues wanted to see if they could detect the effect of these electron correlations in a half-filled, Mott insulating state. They looked to see what would happen if they disturbed the state by moving electrons around. If electron correlations have any effect, such perturbations of electron configurations would meet resistance, since electrons naturally repel each other. For example, an electron that attempts to move to a neighboring well would be pushed back by the electron already occupying that well, even if that well can technically accommodate an additional electron.

In order to overcome this resistance, it would require an extra boost of energy — just enough to overcome the electron’s natural repulsion. The team reasoned that the magnitude of this boost would be a direct measure of the electron correlation’s strength.

The researchers supplied the extra boost using light. They shone light of different colors, or wavelengths, onto the material, and looked for a peak, or a single specific wavelength that the material absorbed. This wavelength corresponded to a photon with just enough energy to kick an electron into a neighboring half-filled well.

In their experiment, the team indeed observed a peak — the first direct detection of electron correlations in this specific moiré superlattice material. They then measured this peak to quantify the correlation energy, or the strength of the electron’s repulsive force. They determined this to be about 20 millielectronvolts, or 1/50 of an electronvolt.

The results show that strong electron correlations underlie the physics of this particular 2D material. Ju says the Mott insulating state is particularly important, as it is the parent state of unconventional superconductivity, the physics of which remains illusive. With this new study, the team has demonstrated that ABC trilayer graphen/hBN moiré superlattice is an ideal platform to explore and engineer the more exotic electrical states, including the unconventional superconductivity.

“Today, superconductivity happens only at very low temperatures in a realistic setting,” notes Ju, who says the team’s optical technique can be applied to other 2D materials to reveal similar exotic states. “If we can understand the mechanism of unconventional superconductivity, maybe we can boost that effect to higher temperatures. This material forms a foundation to understand and engineer even more robust electrical states and devices.”

This research was supported, in part, by the National Science Foundation, the Simons Foundation, and the MIT Skoltech program.

Scientists in each city used the same process to collect white clover samples and test them for a particular chemical anti-herbivore defense compound that also affects their stress tolerance for factors such as extreme heat and weather. Assistant Professor Kaitlin Stack Whitney from RIT’s Department of Science, Technology, and Society led a team of five environmental science students working on a senior capstone project to participate on Rochester’s behalf. In October 2018, they collected 650 samples at 41 sites along a straight path from downtown Rochester to Black Creek Park in North Chili along New York State Route 33A.

“We were picking through this tiny roadside weed, but it’s fascinating how you can unpack these global issues about urbanization and climate change by looking at this very overlooked plant,” said Stack Whitney. “There are these big global forces that are affecting how those plants are growing, what they’re doing, and whether or not they can respond to stresses in that very localized environment.”

The GLUE project was an opportunity for the RIT students to get hands-on, impactful research early in their scientific careers. Environmental science alumna Kristina Chomiak ’19, ’21 MS, who will begin pursuing her Ph.D. in sustainability in the fall, said the collaborative experiment helped solidify her interest in research.

“For me at that point personally I hadn’t had a ton of research experience,” said Chomiak. “It was exciting to be able to follow a protocol and actually conduct this wet lab research. And it was even better that it would be published and would be meaningful to the scientific community.”

Chomiak said she is excited to see the full results of the study and learn how the data they collected in Rochester compares to that found from other cities. She said that locally the team did not find a significant difference in adaptation between the urban and rural areas, but they hypothesize that is because Rochester has more snowfall than other cities involved in the study, meaning the white clover plants are less under attack here.

Participants in the first GLUE study, led by the University of Toronto Mississauga, are now discussing additional ways to leverage the data and organize follow-up studies. Stack Whitney plans to participate in at least five follow-up studies.

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Materials provided by Rochester Institute of Technology. Original written by Luke Auburn. Note: Content may be edited for style and length.