UMD Researchers Study the Intricate Processes Underpinning Gene Expression

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Category: Research News

Published: Monday, August 14 2023 12:28

A new study led by University of Maryland physicists sheds light on the cellular processes that regulate genes. Published in the journal Science Advances, the paper explains how the dynamics of a polymer called chromatin—the structure into which DNA is packaged—regulate gene expression.

Through the use of machine learning and statistical algorithms, a research team led by Professor Arpita Upadhyaya and National Institutes of Health Senior Investigator Gordon Hager discovered that chromatin can switch between a lower and higher mobility state within seconds. The team found that the extent to which chromatin moves inside cells is an overlooked but important process, with the lower mobility state being linked to gene expression.

Notably, transcription factors (TFs)—proteins that bind specific DNA sequences within the chromatin polymer and turn genes on or off—exhibit the same mobility as that of the piece of chromatin they are bound to. In their study, the researchers analyzed a group of TFs called nuclear receptors, which are targeted by drugs that treat a variety of diseases and conditions.

“The nuclear receptors in our study are important therapeutic targets for breast cancer, prostate cancer and diabetes,” explained the study’s first author, Kaustubh Wagh (Ph.D. ’23, physics). “Understanding their basic mechanism of action is essential to establish a baseline for how these proteins function.”

As a result, these findings could have broad applications in medicine.

On the move

The genetic information that children inherit from their parents is contained in DNA—the set of instructions for all possible proteins that cells can make. A DNA molecule is about 2 meters in length when stretched from end to end, and it must be compacted 100,000 times in a highly organized manner to fit inside a cell’s nucleus. To achieve this, DNA is packaged into chromatin in the nucleus of a cell, but that bundle of genetic material doesn’t stay stationary.

“We know that how the genome is organized in the nucleus of our cells has profound consequences for gene expression,” Wagh said. “However, an often-overlooked fact is that chromatin is constantly moving around inside the cell, and this mobility may have important consequences for gene regulation.”

 Researchers discovered that chromatin can dynamically switch between two states of mobility: state 1, in which chromatin moves a shorter distance (shown in red font on the right) and state 2 (shown in blue font on the left). Click image to download hi-res version.

The research team—including collaborators from the National Cancer Institute, the University of Buenos Aires and the University of Southern Denmark—showed that chromatin switches between two distinct mobility states: a lower one (state 1) and a higher one (state 2). Earlier theories suggested that different parts of the nucleus had fixed chromatin mobilities, but the researchers demonstrated that chromatin is much more dynamic.Researchers discovered that chromatin can dynamically switch between two states of mobility: state 1, in which chromatin moves a shorter distance (shown in red font on the right) and state 2 (shown in blue font on the left).

“Previous studies have proposed that different chromatin mobility states occupy distinct regions of the cell nucleus. However, these studies were performed on a sub-second timescale,” said Upadhyaya, who holds a joint appointment in the Institute for Physical Science and Technology. “We extend this model by showing that on longer timescales, the chromatin polymer can locally switch between two mobility states.”

The researchers found that transcriptionally active TFs preferred to bind to chromatin in state 1. They were also surprised to discover that TF molecules in a lower mobility state bound for longer periods of time, likely affecting gene regulation.

Finding a raft in the ocean

This study advances scientists’ understanding of chromatin dynamics and gene expression. The researchers will use their framework to study how mutations affect the function of TFs, which can offer insight into the onset of various diseases.

“We are now in a position to answer whether a particular disease phenotype occurs due to the TF binding for too much or too little time, or not binding in the right chromatin state,” Wagh said.

The team also plans to investigate how TFs achieve the challenging feat of finding their targets. TFs target a specific base pair sequence of DNA, and only by finding and binding this sequence can they recruit other proteins to activate nearby genes.

“A TF finding its target site is like finding a single raft in the middle of the ocean,” Upadhyaya said. “It’s a miracle it even happens, and we plan to figure out how.”

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Their paper, “Dynamic switching of transcriptional regulators between two distinct low-mobility chromatin states,” was published in Science Advances on June 14, 2023.

This work was supported by the National Institutes of Health (Award No. R35 GM145313), National Cancer Institute Intramural Program, NCI-UMD Partnership for Integrative Cancer Research, Center for Cancer Research, National Science Foundation (Award Nos. NSF MCB 2132922 and NSF PHY 1915534), Vissing Foundation, William Demant Foundation, Knud Højgaard Foundation, Frimodt-Heineke Foundation, Director Ib Henriksen Foundation, Ove and Edith Buhl Olesen Memorial Foundation, Academy of Finland, Cancer Foundation Finland, Sigrid Jusélius Foundation, Villum Foundation (Award No. 73288), Independent Research Fund Denmark (Award No. 12-125524), Danish National Research Foundation (Award No. 141) to the Center for Functional Genomics and Tissue Plasticity, CONICET and the Agencia Nacional de Programación Científica y Tecnológica (Award Nos. 2019-0397 and PICT 2018-0573). This story does not necessarily reflect the views of these organizations.

This article is adapted from text provided by Kaustubh Wagh. Originally published here: https://cmns.umd.edu/news-events/news/umd-researchers-study-intricate-processes-underpinning-gene-expression

Media Relations Contact: Emily Nunez
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UMD Lab to Become Major Laser Research Center

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Category: Department News

Published: Tuesday, August 08 2023 08:17

Led by Professor Howard Milchberg, the Lab for Intense Laser-Matter Interactions has been chosen as one of ten LaserNetUS nodes.  The lab will receive an annual award for three years to fund laser lab research staff, postdocs and graduate students.

LaserNetUS was established in 2018 by the US Department of Energy (DOE) and is funded through the DOE’s Office of Fusion Energy Sciences (FES).  The purpose of the network is to allow US and international researchers without access to high powered and unique lasers the ability to  do experiments in cooperation with the network’s facilities.  In return, this leads to the advancement of research and  stimulates collaboration between various research groups.Professor Milchberg's Laser Matter Interactions Group

This year, UMD is one of three new nodes.  As a collaborative node, Milchberg’s lab will accept proposals from other research groups and will have the opportunity to collaborate with those that best fit its scientific agenda.

Milchberg notes that ”this award recognizes our lab’s broad array of laser sources and techniques and its commitment to fundamental physics understanding and student education. This has been the recipe for many well-known Maryland innovations and discoveries” 

Read here for more information on LaserNetUS. 

Original story: https://ece.umd.edu/news/story/umd-lab-to-become-major-laser-research-center

Charles W. Misner, 1932 - 2023

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Category: Department News

Published: Tuesday, July 25 2023 09:38

Charles W. Misner, an eminent theorist and co-author of the classic textbook Gravitation, died on July 24, 2023. He was 91.

Misner received a bachelor’s degree at the University of Notre Dame before his doctoral studies at Princeton University with John Archibald Wheeler.  Following conferral of his Ph.D. in 1957, he remained at Princeton. A Sloan Fellowship enabled him to study at Niels Bohr’s Institute for Theoretical Physics in Copenhagen, and while there, he met and fell in love with Susanne Kemp, a friend of the Bohr family.  John S. Toll, also in Denmark that spring, greeted the couple as they emerged from their wedding at the Copenhagen cathedral to convince them to move to UMD. Toll's powers of persuasion prevailed, and Misner served on the Maryland faculty from 1963 until his 2000 retirement. 

Misner enjoyed a distinguished career in general relativity, devising with Richard Arnowitt and Stanley Deser the ADM formalism, which earned them the American Physical Society Dannie Heineman Prize for Mathematical Physics in 1994, and was commended by the Albert Einstein Society with its Einstein Medal in 2015. Misner was an elected Fellowand was an elected Fellow of the American Academy of Arts and Sciences, the American Physical Society, the American Association for the Advancement of Science and the Royal Astronomical Society. 

He is also well-known as the co-author, with Wheeler and Nobel laureate Kip Thorne, of the acclaimed 1973 textbook, Gravitation. The authoritative opus, known universally as MTW, was so comprehensive and unique in its vivid pedagogical style that it has remained a valued resource despite subsequent developments, and was republished in 2017. Earlier this year, the International Society on General Relativity and Gravitation (ISGRG) celebrated the book’s 50th anniversary with an online forum; the milestone was also marked in Physics Today.

Following LIGO’s confirmation of Einstein’s theory of relativity, Misner contributed to UMD's popular Nov. 1, 2016 symposium, A Celebration of Gravitational Waves.  When Rainer Weiss, Kip Thorne and Barry Barish received the 2017 Nobel Prize for LIGO, Misner was quoted in Nature 's writeup.  His student Richard Isaacson (Ph.D., 1967), was noted as an "unsung hero" of LIGO, along with former UMD physicist Joe Weber and Alessandra Buonanno, in a separate article in Nature. 

The American Institute of Physics interviewed Misner for its oral history collection in 1989, 2001 and in 2020.

In 2018, Susanne Misner spotted a New York Times story announcing that a signed copy of Stephen Hawking's doctoral thesis had sold for $760,000. The Misners authorized the sale of their Hawking correspondence, yielding $260,000 to benefit the Joseph Weber Fund for Gravitational Physics.

More recently, the Misner family established the Charles W. Misner Endowed Lectureship in Gravitational Physics, which debuted in Fall 2022. 

The Charles W. Misner Award, recognizing outstanding Ph.D. thesis work in gravitation and cosmology by a UMD graduate student, was established in his honor.

Susanne Misner died in 2019; the couple is survived by four children and five grandchildren.  Please see this link for further information from the Misner family.  

John Wheeler, Kip Thorne and Charlie Misner.

Front row: Dieter Brill, Bei-Lok Hu, Charlie Misner, Ted Jacobson. Behind them (left to right) are postdoc Jonathan Simon (now a UMD ECE/Biology Professor) and graduate students Tom Shiokawa, Alpan Raval, Greg Stevens, Stephen Ramsey, Nicholas Phillips, Steven Corley, and Gungwon Kang.

Susanne Kemp and Charles Misner at their Copenhagen wedding, June 13, 1959.

Margrethe and Niels Bohr at the Kemp-Misner wedding.

Charlie and Susanne Misner at the physics memorial for John S. Toll.

 

Charlie Misner, John Wheeler, John Toll and Mary Ridgell at the 2001 renaming of the physics building for John Toll. 

David Fiske, Misner and Wheeler at the the 2001 renaming of the physics building for John Toll. 

Misner as rendered by his graduate student, C. V. Vishveshwara. 

Misner with his graduate student, C. V. Vishveshwara. 

One of many physics cartoons produced by “Vishu” Vishveshwara

In 1970, John Wheeler organized a conference in honor of mathematician W.K. Clifford--who first posited that matter is a form of spatial curvature---at the new Jadwin Hall at Princeton U.

Participants included Wheeler, Robert Dicke, Eugene Wigner, Stephen Hawking, Brandon Carter, Cecile DeWitt, Charles Misner, Freeman Dyson, Bryce DeWitt, James York, Arthur Wightman. John Klauder, Tulio Regge, Kip Thorne, James Peebles, Bei-Lok Hu, Dieter Brill, Bill Unruh, Karel Kuchař, Jeffrey Cohen, Brandon Godfrey, Claudio (Teitelboim) Bunster, Remo Ruffini, David Sharp and Nicola Cabibbo.

At the International Symposium on Directions in General Relativity, May, 1993, John Wheeler and Cécile DeWitt-Morette, in front, surround a photo of mathematician W.K. Clifford. Second row: Bei-Lok Hu, Kip Thorne, Dieter Brill, Karel Kuchař, Charles Misner, Bryce DeWitt and James W. York.  (The people and their relative positions in this photo form a subset of those in the previous photo of the 1970 Clifford Conference.)

At his retirement celebration, Misner enjoys remarks by Bei-Lok Hu. Also visible are Jean-Paul Richard and Michael Fisher.

 Front row: Tsvi Piran, Murray Cantor, Deiter Brill, Vince Moncrief

Second row: John Wheeler, Doug Eardley, Charlie Misner, Bei-Lok Hu

Third row: ?, Jeeva Anandan, Jimmy York, Frank Tipler 

Back row: ?, Nick Tsamis, Richard Woodard

Richard Arnowitt, Charlie Misner, Stanley Deser

C.W. Misner, J.A. Wheeler, K.S. Thorne

Dieter Brill, Charlie Misner, Birgit Brill, Francis Misner

Detail from group portrait at the 60th Birthday Symposium honoring Dieter Brill and Charlie Misner. Second row, center: Dennis Sciama, Charles Misner, Dieter Brill, Stanley Deser, ?, John Toll

Dieter Brill, Ted Jacobson, Betty Alexander, Bei-Lok Hu, Charlie Misner, Jonathan Simon

Charles Misner, Claudio Teitelboim (Bunster)

Bei-Lok Hu, Susanne Misner, Charlie Misner, Phil Johnson, Veronika Hubeny, ?, Jorma Louko

Charles Misner, ?, Leslie Fishbone

At the 2016  Celebration of Gravitational Waves: Jim Gates, Kip Thorne, Alessandra Buonanno, Charlie Misner, Peter Shawhan and Rai Weiss.

Charlie Misner at the March 2019 dedication of the Weber Garden outside the PSC. 

Crystal Imperfections Reveal Rich New Phases of Familiar Matter

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Category: Research News

Published: Friday, July 14 2023 12:40

Matter—all the stuff we see around us—can be classified into familiar phases: our chairs are solid, our coffee is liquid, and the oxygen we breathe is a gas. This grouping obscures the nitty gritty details of what each molecule or atom is up to and reduces all that complexity down to a few main features that are most salient in our everyday lives.

But those are not the only properties of matter that matter. Focusing on solids, physicists have found that they can group things according to symmetries. For example, atoms in solids arrange themselves into repeating patterns, forming crystals that can be grouped according to whether they look the same left and right, up and down, rotated about, and more. In the 1980s, physicists discovered a new paradigm: In addition to symmetries, solids can be classified using topology—a field of math that does for geometrical shapes the same kind of thing that symmetries do for crystalline solids. All the shapes without holes (a ball, a pizza) are in the same topological “phase,” while those with one hole (a donut, a coffee mug) are in a different “phase,” and so on with each new hole.

Within physics, topology doesn’t usually refer to the shape a piece of metal is cut into. Rather, the topology of how electrons are arranged inside a crystal provides information about the material’s electrical conductance and other properties. Now, theorists at the Joint Quantum Institute have found that these same crystals hide a richer set of topological phases than previously thought. In two separate works, they revealed a host of possible topological phases that become apparent when two different kinds of defects develop in crystals, or when they study the twirling properties of the electronic arrangement. They published their findings in the journal Physical Review X on July 14, 2023 and in the journal Physical Review Letters in Dec. 2022.

“Condensed matter physics is about understanding all the properties of phases of matter,” says Naren Manjunath, a graduate student at JQI and an author on both results. “I think that our work is really expanding our understanding of how to define new topological properties and how to characterize phases of matter better.”

Topology was first recognized as an important matter-classification tool after the discovery of the quantum Hall effect in the 1980s. When thin sheets of certain materials are pierced by a strong magnetic field, the electrons inside the materials spin around in circles—the larger the magnetic field the tighter their turns. Once the circles get small enough, quantum mechanics kicks in and dictates that the size of the circles can only have certain discrete values (the “quantum” in the quantum Hall effect). As the magnetic field is increased, nothing changes for a while—there is a plateau. Then, when the field gets large enough, electrons suddenly hop into a tighter orbit—an abrupt, step-wise change.

This jump from one radius of a spinning orbit to another can be thought of as a change in the topological phase—the geometry of the electron motion in the material switches. This sudden hopping is extremely precise, and it results in abrupt jumps in the electrical conductivity of the metal sheet, making the topological phase easy to measure experimentally.

Hofstadter butterfly (Adapted from Osadchy and Avron, J. Math. Phys. 42, 5665–5671 (2001) https://doi.org/10.1063/1.1412464 )

Even more interesting things would happen if the magnetic field in the quantum Hall effect was cranked up so high that the electron orbitals became about as small as the atomic spacing in the crystal. There, electrons arrange themselves into different topological phases that depend on how many electrons were around in the first place and the magnetic field piercing each little bit of the crystal. A color-coded plot of conductivity as it depends on the electron density and the magnetic field appears as a winged butterfly, called the Hofstadter butterfly after the theoretical physicist that first studied this model.

“We're furthering this program of trying to find all possible quantized numbers that could be associated with phases of matter,” says JQI Fellow and Associate Professor Maissam Barkeshli, a principal investigator on the work. “And this is a long-term program and we made a lot of progress on it recently.”

Manjunath, Barkeshli, and their collaborators found that there may be more intricate details hiding in the Hofstadter butterfly’s wings than previously thought. Some spots on the butterfly might have the same color, and therefore the same topological phase in the original treatment, and yet behave differently from each other in important ways.

These extra distinguishing features are always present, but they become most obvious when the crystal develops defects—little mistakes in its otherwise perfectly regular pattern. The way electrons behave around this defect would differ depending on the underlying topological phase. And different defects can help uncover different kinds of phases.

The team first studied an imperfection called a disclination, which occurs when a piece of the crystal is taken out and the remaining atoms are stitched back together, as seen in the diagram below. The researchers found that electric charge tends to cluster around this defect. And how much charge pops up at the defect depends on a new quantity, which the team called the shift. Much like the size of electron orbits in the quantum Hall effect, the shift is quantized: It can only be an integer or a half-integer. A different value of the shift corresponds to a different phase of matter. The electric charge appearing at a disclination would be a multiple of this shift, which, weirdly enough, could even be a fraction of a single electron’s charge. They published the results of their theoretical investigation in the journal Physical Review Letters in December 2022.

After disclinations, the team focused their attention on another kind of imperfection called a dislocation. Unlike a disclination, no atoms are missing in a dislocation. Instead, the connections between atoms in a crystal are rewired in a different order. Instead of being connected to its closest neighbor, one or more of the atoms bonds with the next atom over, creating a skewed ladder of links.

Dislocations turned out to have another quantized quantity associated with them, this time named a quantized polarization. Inside a perfectly regular crystal, every tiny square of the lattice may hide a bit of charge polarization—one side becomes somewhat positively charged while the other side becomes a bit negatively charged. This polarization is hard to spot. If a dislocation is introduced, however, the researchers found that one side of this polarized charge gets trapped in the defect, revealing the extent of the polarization. Exactly how polarized they would become depended directly on the underlying quantized polarization. The team published this result in the journal Physical Review X.

Each of these quantities—the shift and the quantized polarization—has consequences even without any defects. These consequences have to do with the way the electrons tend to twist around different points inside the crystal lattice. But these twists are tricky to find experimentally, while crystal defects offer a tangible way of measuring and observing these new quantities by trapping charges in their vicinity.

New butterflies, cousins of the original Hofstadter butterfly, pop up thanks to the shift and quantized polarization. Both can be plotted as a function of electron density and magnetic field and exhibit the same winged, fractal butterfly-like structure. The researchers believe more such quantities and their associated phases remain to be uncovered, associated with yet more defects. “Eventually we expect we will have a large number of beautiful colored butterfly figures,” Barkeshli says, “one for each of these topological properties.”

For now, testing these predictions experimentally seems just out of reach. The Hofstadter model requires such large magnetic fields that it cannot be realized in regular materials. Instead, people have resorted to simulating this model with synthetic lattices of atoms or photons, or in layered graphene structures. These synthetic lattices are not quite large enough to measure the charge distributions required, but with some engineering advances, they might be up to the task in the coming years. It may also be possible to create these lattices using small, noisy quantum computers that have already been built, or topological photonic systems.

“We only considered the Hofstadter model,” says Manjunath, “but you could measure the same thing for more exotic phases of matter. And some of those phases might actually have some applications in the very distant future.”

Original story by Dina Genkina: https://jqi.umd.edu/news/crystal-imperfections-reveal-rich-new-phases-familiar-matter

In addition to Manjunath and Barkeshli, authors on the publications included UMD graduate students Yuxuan Zhang and Gautam Nambiar.

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