Groundbreaking Work from Dekker Lab

Job Dekker (Project 2) and his colleagues, with support from the CR-PSOC, have just published an important paper in Science on activation of proto-oncogenes by disruption of chromosome neighborhoods.  “Activation of proto-oncogenes by disruption of chromosome neighborhoods”. This finding ties to work from Vadim Backman (Project 3, Nanocytometry Core) showing an increase in nanoscale nuclear disorder during carcinogenesis.

See also this link for commentary: http://science.sciencemag.org/content/351/6280/1398?utm_campaign=email-sci-toc&et_rid=33803649&et_cid=364259

CR-PSOC Leader Advises on President’s Cancer Moonshot 2020

On March 25th, Thomas V. O’Halloran (Chemistry) addressed the President’s Council of Advisors on Science and Technology (PCAST) on the “cancer moonshot” initiative described by President Obama in his State of the Union address.  O’Halloran was asked to address the Council in his capacity as director of the Chicago Region Physical Science-Oncology Center.  His talk focused on the need to integrate large scale teams of oncologists and cancer biologists with researchers in the physical sciences, complex systems, data mining and materials sciences.  Current cancer research is concentrated upon molecular pathways involved in cancer and is driven by cancer researchers trained in the life sciences.  He proposed the creation of a large scale national network of centers that will collaborate on early diagnosis and treatment of cancer using the tools and perspectives of the physical sciences.

This proposal has its genesis in the successes of Northwestern’s Chemistry of Life Processes Institute in large-scale team science built on collaboration among scientists and clinicians across a broad range of disciplines.  A remarkable aspect of this capability is the Institute’s ability to “plug and play” diverse teams across a broad range of important biomedical topics.

View video of Director O’Halloran’s address at the following web address. His talk starts at the 22 minute mark. http://tvworldwide.com/events/pcast/160325/globe_show/default_go_archive.cfm?gsid=2941&type=flv&test=0&live=0

Computational Approach Shows “Noise” Can Influence Intracellular Networks

A cell’s life is a noisy affair. These building blocks of life are constantly changing. They can spontaneously express different proteins and genes, change shape and size, die or resist dying, or become damaged and cancerous. Even within a population of the same type of cell, there is immense random variability between cells’ structures, levels of protein expression, and sizes.

“High dimensionality and noise are inherent properties of large intracellular networks,” said Adilson E. Motter, the Charles E. and Emma H. Morrison Professor of Physics and Astronomy at Northwestern University, and Chicago Region Physical Sciences Oncology Center Co-Investigator. “Both have long been regarded as obstacles to the rational control of cellular behavior.”

Motter and his collaborators at Northwestern have challenged and redefined this long-held belief. Using a newly-developed computational algorithm, they showed that this randomness within and among cells, called “noise,” can be manipulated to control the networks that govern the workings of living cells — promoting cellular health and potentially alleviating diseases such as cancer.

Supported by the National Cancer Institute Physical Science-Oncology Center at Northwestern and the National Science Foundation, the research is described in the September 16 issue of the journal Physical Review X. Motter and William L. Kath, professor of Engineering Sciences and Applied Mathematics, are coauthors of the paper. Daniel K.Wells, a graduate student in applied math, is the paper’s first author.

“Noise refers to the random aspects of cell behavior, especially gene regulation,” Wells said. “Gene regulation is not like a train station, where gene expression-regulating proteins are shipped in at regular intervals, turn a gene on or off, and then are shipped out. Instead, gene expression is constantly, and randomly, being modified.”

By leveraging noise, the team found that the high-dimensional gene regulatory dynamics could be controlled instead by controlling a much smaller and simpler network, termed a “network of state transitions.” In this network cells randomly transition from one phenotypic state to another — sometimes from states representing healthy cell phenotypes to unhealthy states where the conditions are potentially cancerous. The transition paths between these states can be predicted, as cells making the same transition will typically travel along similar paths in their gene expression.

The team compares this phenomenon to the formation of pathways at a university campus. If there is no paved path between a pair of buildings, people will usually taken the path that is the easiest to traverse, tromping down the grass to reveal the dirt beneath. Eventually, campus planners may see this pre-defined path and pave it.

Similarly, upon initially analyzing a gene regulatory network the team first used noise to define the most-likely transition pathway between different system states, and connected these paths into the network of state transitions. By doing so the researchers could then focus on just one path between any two states, distilling a multi-dimensional system to a series of one-dimensional interconnecting paths.

“Even in systems as complex and high-dimensional as a gene regulatory network, there’s typically only one best path that a noisy transition will follow from one state to the next,” Kath said. “You would think that many different paths are possible, but that’s not true: one path is much better than all of the others.”

The team then developed a computational approach that can identify optimal modifications of experimentally-adjustable parameters, such as protein activation rates, to encourage desired transitions between different states. The method is ideal for experimental implementations because it changes the system’s response to noise rather than changing the noise itself, which is nearly impossible to control.

“Noise is extremely important for systems,” Wells said. “Instead of directly controlling a cell to move from a bad state to a good state, which is hard, we just make it easier for noise to do this on its own. This is analogous to paving just one path departing a building and leaving all the others unpaved–people leaving the building are more likely to walk on the paved path, and will thus preferentially end up where that path goes.”

Though the current research is theoretical and focuses on biological networks, the team posits that this strategy could be used for other complex networks where noise is present, like in food webs and power grids, and could potentially be used to prevent sudden transitions in these systems, which lead to ecosystem collapses and power grid failures.

The above post is reprinted from materials provided by Northwestern University. The original item was written by Amanda Morris.

Peng Ji Receives 2015 Young Physician-Scientist Award

Peng Ji, recipient of a PS-OC Outreach Pilot Project Award, received the 2015 Young Physician-Scientist Award from the American Society for Clinical Investigation.

Peng Ji, MD, PhD, ’13 GME, assistant professor in Pathology, was recently honored with one of the American Society of Clinical Investigation’s (ASCI) 2015 Young Physician-Scientist Awards. He is one of only 40 investigators nationwide to receive the honor this year.

“I feel very honored to receive this award and to be recognized among a prestigious group of young investigators,” Dr. Ji said.

Dr. Ji has made significant contributions in the fields of pathology and hematology. In a recent paper published in Blood, Dr. Ji and his colleagues discovered several genetic mutations associated with the development of Myelodysplastic syndromes (MDS), a group of diseases that affect bone marrow and lead to ineffective production of stem cells that become blood cells.

His lab discovered that the disease was associated with the loss of parts of chromosome 5, which in turn led to abnormal overexpression of the CD14 gene and contributed to the development of MDS.

Dr. Ji said that working on research both in a lab and clinical setting allows him to better treat his patients and recognize disease patterns in his research.

“When I started my post-doc training, I started to see there was a disconnect between basic science and clinical medicine,” Dr. Ji said. “I knew I needed to use my clinical training and knowledge to guide my basic science research.”

In addition to receiving the award, he is also finishing a clinical residency in pathology and pursuing research in his lab. He has been awarded The American Society of Hematology Scholar Award, The Chicago Biomedical Research Consortium Catalyst Award, the Department of Defense Career Development Award and recently an NIH R01 grant award for his study in terminal erythropoiesis.

The Young Physician Scientists Award is given to faculty who are supported by any NIH K award or equivalent, are early in their first faculty appointment and have made notable achievements in their research. Recipients were presented with their awards at a celebratory dinner in April.

Written by Amber Bemis and originally posted by the Northwestern University Feinberg School of Medicine News Center.

National Cancer Institute awards Northwestern nearly $10 million for cancer research

EVANSTON, Ill. — Northwestern University has received a five-year, $9.6 million grant from the National Cancer Institute (NCI) for a new Physical Science-Oncology Center that unites physical scientists and cancer researchers from Northwestern, the University of Chicago and University of Illinois at Chicago.

The Chicago Region Physical Science-Oncology Center (CR-PSOC) is part of a larger coalition assembled by the NCI to bring breakthroughs in the physical sciences to bear on the complex problem of cancer. Only four such centers have been funded across the nation this year.

“Cancer patients expect us to increase the speed with which we apply discoveries in the basic sciences to prevention, detection and treatment,” said Northwestern’s Thomas V. O’Halloran, the CR-PSOC’s principal investigator. “The center’s mission is to advance our understanding of cancer by examining the role of physical and chemical forces involved in transforming a normal cell into a cancer-causing cell.”

This is the second PS-OC at Northwestern. The first center, under the leadership of the late Jonathan Widom and Dr. Jonathan D. Licht, was funded in 2009 for five years. That innovative work led to the CR-PSOC’s expanded research scope and interdisciplinary collaborations with researchers across Chicago and the country.

“The National Cancer Institute expects these centers to stimulate the flow of new ideas, diagnostic methods and therapeutic approaches between the physical science and cancer research communities,” said O’Halloran, the Morrison Professor of Chemistry in the Weinberg College of Arts and Sciences.

O’Halloran, a physical scientist, and Licht, a cancer researcher and the Dobe Professor of Hematology-Oncology at Northwestern University Feinberg School of Medicine, will lead the CR-PSOC. Both are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

“What we’re trying to do is understand the fundamental rules of misbehavior of cancer cells with a particular class of mutations,” Licht said. “The center is reaching beyond genomics into the rapidly growing areas of epigenetics and metallomics.”

Scientists have long known that the transformation of healthy cells to cancer cells involves more than just mutations in our genetic DNA sequence. The CR-PSOC team will develop new ways to interrogate changes in the “epigenome” (the chemical markers that influence the folding and condensation of DNA within the nucleus) and changes in the “metallome” (the metal ion content of the cell) that support the development of cancer.

The “packaging” of DNA influences the local environment of genes and their regulation, O’Halloran explained. DNA is packaged together with proteins, RNA and metal ions into a structure known as chromatin, which is responsible for DNA folding and plays a vital role in gene expression.

CR-PSOC investigators will deploy a series of physical science approaches and novel imaging methods to determine whether changes in chromatin folding result in aberrant patterns of gene expression that drive cancer progression. Then, the researchers will translate these advances into a deeper understanding of cancer biology and, eventually, into novel cancer therapy.

The core Chicago-area team is composed of 12 physical scientists and eight cancer researchers from fields including physics, chemistry, biomedical engineering, biophysics, biochemistry, pharmacology and hematology-oncology from Northwestern, UChicago and UIC.

CR-PSOC project leaders have recruited additional experts in the physical sciences and chromatin fields from outside Chicago, namely from Massachusetts Institute of Technology, Memorial-Sloan Kettering Cancer Center and the University of Massachusetts Medical School.

“Thought leaders in the physical sciences and oncology fields have joined forces to share emergent ideas and cutting-edge methods and use them to understand molecular changes that allow cancer cells to grow out of control,” O’Halloran said. “By combining interdisciplinary strengths, this team hopes to make significant progress in the diagnosis and treatment of several types of cancer.”

Designed around the theme of “Spatio-Temporal Organization of Chromatin and Information Transfer in Cancer,” the center consists of three interrelated project areas, each focused on different aspects of chromatin structure and function, plus two core facilities and pilot project, education and outreach programs.

The center will be a knowledge hub for training the next generations of scholars to make breakthroughs at the convergence of physical sciences and oncology. Center programming will include an extensive series of workshops, student forums, symposia and journal clubs.  An institutional commitment by Northwestern to support the training of graduate students and postdoctoral fellows engaged in CR-PSOC research will further extend the center’s educational reach.

The CR-PSOC is supported by the resources and expertise of Northwestern’s foremost engines for transdisciplinary research, the Chemistry of Life Processes Institute and the Lurie Cancer Center, as well as by resources of UChicago and UIC.

In addition, a Chicago Biomedical Consortium (CBC) Lever Award of $1.5 million will support the center and its acquisition of new instrumentation and shared resources. These research capabilities also will be available to researchers across the region.

A full list of CR-PSOC investigators can be found on the center’s website.

Read full story as written by Megan Fellman on Northwestern News.

CBC Announces Sixth Lever Award

Chicago Biomedical Consortium Lever Award Supports Center’s New Instrumentation and Shared Resources

Vadim Backman (NU), Lucy Godley (UChicago) and Jack Kaplan (UIC) are co-Principal Investigators on the CBC’s new $1.5M Lever Award:  “Chicago Center for Physical Science-Oncology Innovation and Translation.”  Professors Backman, Godley, and Kaplan are members of a team led by Thomas O’Halloran (NU) and Jonathan Licht (NU) which recently won a $10M NCI U54 grant to fund the Chicago Region Physical Science-Oncology Center.  CBC Lever funds will support the Center’s new instrumentation and shared resources.

Scientists have long known that the transformation of healthy cells to cancer cells involves more than just mutations in our genetic DNA sequence. Now, thanks to a $10M grant from the National Cancer Institute, researchers in the Chicago Region Physical Science–Oncology Center (CR-PSOC) will advance our understanding of this disease by examining the role of physical and chemical forces involved in the transformation of a normal cell into a cancer-causing one. This team will develop new ways to interrogate changes in the “epigenome”— the chemical markers that influence the folding and condensation of DNA within the nucleus, and changes in the “metallome” – the metal ion content of the cell— that support the development of cancer.

The “packaging” of DNA influences the local environment of genes and their regulation. DNA is packaged together with proteins, RNA and metal ions into a structure known as chromatin which is responsible for DNA folding and plays a vital role in gene expression. CR-PSOC investigators will deploy a series of physical science approaches and novel imaging methods to determine whether changes in chromatin folding result in aberrant patterns of gene expression that drive cancer progression. Then, they will translate these advances into a deeper understanding of cancer biology and, eventually, into novel cancer therapy.

The Center is led by a pair of Northwestern researchers. Renowned physical scientist Thomas V. O’Halloran, PhD, Morrison Professor of Chemistry in the Weinberg College of Arts and Science and Director of Northwestern’s Chemistry of Life Processes Institute (CLP), is principal investigator. Collaborating with him is internationally recognized cancer researcher Jonathan D. Licht, MD, Director of the Division of Hematology and Oncology and Dobe Professor of Hematology-Oncology in the Feinberg School of Medicine.  They are both members of Northwestern’s Robert H. Lurie Comprehensive Cancer Center.

The CR-PSOC is composed of a multi-disciplinary team of 12 physical scientists and 8 cancer researchers from fields encompassing physics, chemistry, biomedical engineering, biophysics, biochemistry, pharmacology, and hematology-oncology from the Chicago region’s premier research institutions: Northwestern University, the University of Chicago and University of Illinois at Chicago.  Project leaders recruited additional experts in the physical sciences and chromatin fields from outside Chicago, namely MIT, Memorial-Sloan Kettering Cancer Center, and the University of Massachusetts Medical School.

“Several thought-leaders in the physical sciences and oncology fields have joined forces to bring emergent ideas and cutting-edge methods and focus them on understanding  molecular changes that allow the cancer cell to grow out of control,” said Dr. O’Halloran (right). “By harnessing these combined interdisciplinary strengths, this team will make significant progress in the diagnosis and treatment of several types of cancer.”

Designed around the theme of “Spatio-Temporal Organization of Chromatin and Information Transfer in Cancer,” the Center consists of three interrelated project areas, each focused on different aspects of chromatin structure and function, plus two core facilities, and pilot project, education and outreach programs.

“What we’re trying to do is understand the fundamental rules of misbehavior of cancer cells with a particular class of mutations,” said Dr. Licht (left).

The Center will be a knowledge hub for training the next generations of scholars to make breakthroughs at the convergence of physical sciences and oncology. Center programming will include an extensive series of workshops, student forums, symposia, and journal clubs.  An institutional commitment by Northwestern University to support the training of graduate students and postdocs engaged in CR-PSOC research will further extend the Center’s educational reach.

The Center is part of a cadre of Physical Science-Oncology Centers within the National Cancer Institute’s collaborative Physical Sciences-Oncology Network.

“We will have common cellular platforms, and we’re going to have frequent group meetings, as well as periodic regional and national meetings where these findings are discussed and where inter-program collaboration is encouraged,” said Dr. Licht. “We will have a kickoff meeting in mid-July.”

The Center is supported by the resources and expertise of Northwestern’s foremost engines for transdisciplinary research: CLP and the Robert H. Lurie Comprehensive Cancer Center. The breadth and scope of these resources will be substantially augmented by local consortium partners, the University of Chicago and University of Illinois at Chicago, and through a $1.5M Lever grant from the Chicago Biomedical Consortium that provides additional support for key shared resource facilities (see below). Vadim Backman (NU), Lucy Godley (UChicago) and Jack Kaplan (UIC) are co-Principal Investigators on the CBC’s Lever Award: “Chicago Center for Physical Science-Oncology Innovation and Translation.”

“This new Center is part of a coalition assembled by the National Cancer Institute to address and bring breakthroughs in the physical sciences to bear on the problem of cancer” said Dr. O’Halloran. “Cancer patients expect us to increase the speed with which we apply discoveries in the basic sciences to the prevention, diagnosis and treatment of disease, and the PS-OC teams are embracing this important challenge.”

– – –

Adapted with modifications from: “New $10M Chicago Region Physical Science-Oncology Center Will Expand Personalized Medicine Beyond the Genome”. Press Release, Northwestern’s Office for Research, May 20, 2015. Contact: Sheila Judge s-judge@northwestern.edu  847-491-5868

– – –

The CBC Lever award will support the following resource facilities:

  • Nanocytometry Core (Northwestern)
    Leader: Vadim Backman
    It will include Partial Wave Spectroscopy (PWS) and Stochastic Optical Reconstruction Microscopy (STORM) for high resolution microscopy
  • PDX Core (Northwestern)
    Leader: Andrew Mazar
    a. Patient-derived xenografts will provide meaningful models of human cancer and enable translation of PSOC innovations
    b. Includes funding for investigator pilot studies using PDX models
  • New high precision methylation analysis capabilities through acquisition of an Illumina NextSeq500, to be used in the University of Chicago’s Genomics Core
    Leader: Lucy Godley
  • New ultra-sensitive IC-ICP-mass spectrometer capability to be used in the Quantitative Bioelement Imaging Center at Northwestern
    Leader: Thomas O’Halloran

CR-PSOC Co-Investigator, Job Dekker, named an HHMI Investigator at UMASS

Job Dekker becomes seventh Howard Hughes Medical Institute investigator at UMass Medical School

A pioneer in the study of the three-dimensional structure of the genome, Job Dekker, PhD, professor of biochemistry & molecular pharmacology and co-director of the Program in Systems Biology, was named a Howard Hughes Medical Institute (HHMI) investigator. Dr. Dekker, developer of the chromosome conformation technologies used to map the topography of the genome, was one of 26 scientists chosen for his scientific excellence from a pool of 894 applicants. Over the next five years, HHMI has committed $153 million to support these innovative scientists.

“This is one of the most prestigious and sought-after scientific awards in the world. The Howard Hughes Medical Institute recognizes exceptionally creative thinkers and innovative scientists who are at the forefront of expanding the boundaries of scientific knowledge,” said Chancellor Michael F. Collins. “This award allows Dr. Dekker the freedom to pursue novel ideas that can fundamentally change our understanding of disease. All of us at UMMS are incredibly proud of what he has accomplished.”

“It is a tremendous honor to be named among such an accomplished group of scientists,” said Dekker. “Being an HHMI investigator provides us with the resources to pursue game-changing questions about how chromosome structure affects disease formation. With this support we’ll be able to investigate high-risk, high-reward research, such as the kind that led to the initial development of chromosome conformation capture technology.”

Although DNA is comprised of a linear sequence of bases, it doesn’t exist inside the cell nucleus in a simple, straight form. More like a ball of cooked spaghetti, the genome folds and loops back on itself so it can fit inside the tight confines of the nucleus. How the genome is packed inside the nucleus is tightly controlled and varies from cell type to cell type. And each unique shape has a profound influence on which genes in a cell are turned on or turned off.

Seeking tools and technology for mapping the three-dimensional structure of the genome in detail, Dekker developed a biochemical technique for determining how DNA segments interact and are linked to one another. The result, akin to a “molecular microscope,” can be used to detect physical interactions between DNA segments. The more interactions between segments, the more closely associated in space they are, due to chromosome folding. This breakthrough discovery was the genesis of what are now termed “3C,” “5C” and “Hi-C” tools, used by researchers worldwide interested in mapping the structure and organization of chromosomes inside cells.

“Before 3C, we could see that genomes looked different across cell types, but limitations in imaging technologies meant we couldn’t study these differences in a meaningful way,” said Dekker. “Chromosome conformation capture technologies have rapidly taken hold and allowed our lab and others to explore the structure of the genome in a way that wasn’t previously available to scientists.”

Since joining UMMS, Dekker has refined and enhanced the initial chromosome conformation techniques to visualize whole genomes, combining it with next-generation sequencing to create high through put versions.

Dekker has made a number of key discoveries related to how the structure of a genome may influence genetic function and contribute to human disease. Included among these discoveries is the identification of a new mechanism involving chromatin loops that is responsible for controlling genomic structure and activating genes to generate specific cell types. He has also found that chromosomes fold in a series of contiguous “yarns” that harbor groups of genes and regulatory elements, bringing them in contact with each other and allowing them to work in a coordinated manner during development. Recently Dekker and co-workers also uncovered how chromosomes are condensed inside mitotic chromosomes, which are among the most iconic structures in the cell.

In 2012, a team led by Dekker offered conclusive evidence that the three-dimensional structure of the chromosome strongly influences patterns of chromosome rearrangements and translocations, shedding light on a fundamental process related to cancer and our understanding of cancer genomics.

A member of the UMMS faculty since 2003, Dekker received his doctoral degree in biochemistry from Utrecht University in the Netherlands. He trained as a postdoctoral fellow at Harvard University with Nancy Kleckner, PhD, studying chromosome structure and developing the techniques that led to the 3C technology.

Dekker was elected to the American Association for the Advancement of Science in 2014. In 2007, he was named a Keck Foundation Distinguished Young Scholar in Biomedical Research, and he received the 2011 ASBMB Young Investigator Award from the American Society of Biochemistry and Molecular Biology.

HHMI encourages its investigators to push their research fields into new areas of inquiry. By employing scientists as HHMI investigators—rather than awarding them research grants—HHMI gives scientists the freedom to explore and, if necessary, to change direction in their research. Moreover, they have support to follow their ideas through to fruition—even if that process takes many years.

“Scientific discovery requires original thinking and creativity,” says HHMI President Robert Tjian. “Every scientist selected has demonstrated these qualities. One of the most important things we can do at HHMI is to continue to support and encourage the best discovery research. We don’t know this for certain, but the ideas that emerge from these labs might one day change the world, and it’s our privilege to help make that happen.”

HHMI will provide each investigator with his or her salary, benefits and a research budget over an initial five-year appointment. The Institute will also cover other expenses, including research space and the purchase of critical equipment. HHMI appointments may be renewed for additional five-year terms, contingent on a successful scientific review.

Mid-career researchers with five to 15 years of experience as faculty members at more than 200 institutions were eligible to apply. Applications from the 894 eligible applicants were evaluated by distinguished biomedical researchers, who narrowed the field to 59 semifinalists. The semifinalists attended a scientific symposium at HHMI’s Janelia Research Campus in April and presented a brief research talk to members of the review panel. The 26 new HHMI investigators were selected shortly after the scientific symposium.

Through its flagship HHMI Investigator Program, the Institute has joined with more than 70 distinguished U.S. universities, hospitals, institutes and medical schools to create an environment that provides flexible, long-term support for approximately 330 Hughes investigators and members of their research teams. HHMI investigators are widely recognized for their creativity and research accomplishments: 182 HHMI investigators are members of the National Academy of Sciences and there are currently 17 Nobel laureates within the investigator community.

Written by Jim Fessenden and originally posted by the UMASS Medical School Communications

Age-associated alterations in the micromechanical properties of chromosomes in the mammalian egg

A Northwestern University Physical Sciences-Oncology Center outreach pilot project lead to a novel physical approach that shows aging-related changes in the micromechanical properties of meiotic metaphase II chromosomes in mouse oocytes are associated with deleterious in chromosome duplication and egg quality.  In collaboration with UC Berkeley, National University of Singapore and the University of Kansas Medical Center, scientists from the Woodruff and Marko research groups designed and implemented a novel approach to measure the stiffness of chromosomes.

Using this technique, the scientists discovered a correlation between the stiffness of chromosomes and the reproductive age of a model organism. It is widely accepted that signs of aging of the female reproductive system include errors in chromosome segregation leading to a phenomenon named aneuploidy, a condition where there are more or less chromosomes than is normal for that species. In order to investigate the biophysical properties of chromosomes, scientists utilized this stress technique to determine how “stiff” the chromosomes are for both reproductively aged organisms (where there is a high incidence of aneuploidy) and young organisms (where there is a low incidence of aneuploidy). The correlation, as it was discovered, suggests that as the reproductive age of the organism increases, the stiffness of the chromosome also increases. In fact, chromosomes of reproductively old mice required 2.5 times more force to be stretched than the chromosomes of young mice.

This new finding adds great value to the understanding of cancer biology and age related diseases in which errors of chromosome segregation and aneuploidy play crucial roles.

J Assist Reprod Genet. 2015 Mar 11. [Epub ahead of print] Age-associated alterations in the micromechanical properties of chromosomes in the mammalian egg. Hornick JE1, Duncan FESun MKawamura RMarko JFWoodruff TK.

Read full study here.

Jiping Wang to speak at 1st Modeling Cancer Meeting

jiping-wang.jpgJiping Wang, leader of the NU-PSOC Bioinformatics Core, will speak on Modeling causalities of mixed features in TCGA data using Bayesian network analysis at the 1st Annual ICBP/PSOC Mathematical and computational modeling meeting entitled, Modeling Cancer: Integrating Scales, Disciplines and Programs on February 25th in Tampa, FL. The three day meeting is sponsored by NCI¹s Integrative Cancer Biology Program (ICBP) & Physical Sciences in Oncology programs. The limited attendance format will enable participants to discuss theoretical tools and approaches in greater depth than is usually possible in larger program meetings with the goal of building a community resource in this topic area.

Wang is an associate professor and director of graduate studies in the department of physics. His NU-PSOC-funded research has deployed bioinformatics and computational biology aims to develop complex statistical methods for analysis of high throughput genomic and genetic data. His current projects include Expressed Sequence Tag (EST) data analysis, nucleosome sequence alignment and positioning prediction, human brain mapping, DNA methylation differentiation and tRNA inter-positional association. He has developed multiple software tools to support these efforts that he freely shares, including: ESTstat (EST), NuPoP (nucleosome) and SPECIES (species number estimation). Sample publications associated with his role in the NU-PSOC include:

1. Popovic, R., Martinez-Garcia, E., Giannopoulou, E., Zhang, Q., Ezponda, T., Shah, M.Y., Zheng, Y., Will, C.M., Small, E.C., Hua, Y., Bulic, M., Jiang, Y., Carrara, M., Calogero, R.A., Kath, W.L., Kelleher, N.L., Wang, J.-P., Elemento, O. and Licht, J.D., Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation, PLoS Genetics 2014,10(9): e1004566, doi: 10.1371/journal.pgen.1004566 .

2. Small, E.C., Xi, L., Wang, J.-P., Widom, J., and Licht, J.D., Single-cell nucleosome mapping reveals the molecular basis of gene expression heterogeneity. PNAS 2014,111(24):E2462-71,doi: 10.1073/pnas. 1400517111.

3. Henikoff, S., Ramachandran, S., Krassovsky, K., Bryson, E.D., Codomo, C.A., Brogaard, K., Widom, J., Wang, J.-P., Henikoff, J.G., The budding yeast centromere DNA element II wraps a stable Cse4 hemisome in either orientation in vivo, eLife, 2014, 3:e01861.

4. Xi, L., Brogaard,K., Zhang, Q., Lindsay, B.G., Widom, J., and Wang, J.-P., A locally convoluted cluster model for nucleosome positioning signals in chemical map, Journal of American Statistical Association 2014, 109 (505):48-62, DOI:10.1080/01621459.2013.862169

5. Moyle-Heyrman, G., Zaichuk, T., Xi, L., Zhang, Q., Uhlenbeck, O.C., Holmgren, R., Widom, J. and Wang, J.-P., Chemical map of Schizosaccharomyces pombe reveals species-specific features in nucleosome positioning. PNAS 2013,110(50),20158-20163 pdf; Supplementary materials

6. McCallum, K.J. and Wang, J.-P., Quantifying copy number variations using a hidden Markov model with inhomogeneous emission distributions. Biostatistics 2013, Jul;14(3):600-11. doi: 10.1093/ biostatistics/kxt003

7. Nalabothula,N., Xi,L., Bhattacharyya,S., Widom,J., Wang, J.-P., Reeve,NJ, Santangelo, JT, Fondufe-Mittendorf, NY, Archaeal nucleosome positioning in vivo and in vitro is directed by primary sequence motifs. BMC Genomics 2013, 14:391 PDF

8. Yigit, E., Zhang, Q., Xi, L., Grilley, D., Widom, J., Wang, J.-P., Rao, A. and Pipkin, M.E. High-resolution nucleosome mapping of targeted regions using BAC-based enrichment. Nucleic Acids Res. 2013;doi: 10.1093/ nar/gkt081 PDF;Supplementary materials

9. Brogaard, K., Xi, L., Wang, J.-P., and Widom, J., A chemical approach to mapping nucleosomes at base pair resolution. Methods Enzymol. 2012;513:315-34

10. Brogaard, K., Xi, L., Wang, J.-P., and Widom, J., A map of nucleosome positions in yeast at base-pair resolution Nature, 2012, 486: 496­501. Online Supplementary Methods; Other supplementary materials

Trainee Nir Yungster Wins Poster Award

nir_0Trainee Nir Yungster (Project 4), a graduate student working in the Research on Complex Systems group, received an award for his poster “Optimizing Rate Constants in Epigenetic Markov Models” at the 2013 PS-OC Annual Investigators’ Meeting.  Yungster was one of six recipients of the award out of 129 presenters.  Here is Nir’s research in his own words:

Describe your research in general terms.

I presented work on a mathematical model that describes the dynamics of histone modifications in cancer cells.  Histones are proteins that act as spools, allowing DNA to coil into a more compact form.  Through a number of mechanisms, these proteins can significantly impact gene expression in a manner dependent on chemical modifications made to them.  Cancers such as B-cell lymphoma and multiple myeloma have both been linked to proteins that modify these histones, and thus understanding the dynamics of this system can provide important insight into possible treatments for patients.  Our model uses experimental data to quantify the rates at which modifications occur in cancer cells, and allows for dependence on the current modified state of the histone.

How did the PS-OC help shape or develop this research?

My advisor and Project-4 leader Bill Kath and I have been fortunate to find a terrific set of collaborators in Neil Kelleher and Yupeng Zheng, without whom this work would not be possible. The model I presented was a natural outgrowth of their groundbreaking ‘M4K’ approach for tracking the kinetics of histone modification in human multiple myeloma cells as part of a PSOC Pilot Project. Bringing together their top-down proteomics expertise with our mathematical modeling background has made for a fruitful partnership, and our work together continues to grow as both the experimental and modeling sides of the project mature.

markovposterb

What is the next step?

While thus far we have only modeled a small subset of possible histone modifications, our model can be robustly extended to include a larger number of modifications in order to provide a fuller picture of histone modification kinetics. Additionally, by comparing the histone kinetics in cancer cells to the kinetics in normal ones, we hope to use our model to predict treatments that could promote transitions of cancer cells to their non-cancerous forms.

Full Abstract: Recently, a method was developed for conducting M4K – mass spectrometry-based measurement and modeling of histone methylation kinetics (Zheng 2012). We have made improvements to this method by incorporating previously unused experimental statistics into our model-optimization procedure that results in significantly improved fits to experimental data. Accurately modeling methylation changes to histone proteins is essential to understanding the activities of methyltransferases such as EZH2, which has been linked to human B-cell lymphoma, or MMSET, which has been linked to multiple myeloma (MM). Among MM patients, 15-20% show a t(4:14) chromosomal translocation which leads to the overexpression of MMSET. Zheng et. al. used MM cells with high MMSET expression to demonstrate the potency of their M4K approach. By comparing the results from a targeted knock-out of MMSET to a non-targeted knock-out, they obtain a measured decrease in methylation rates. Our model, with its improved modeling of such rates, can be incorporated in testing the effectiveness of drug therapies that might target the activities of methyltransferases. Among the adjustments we made to improve the calculation of these rates was an alteration to the optimization cost function to weigh deviations between our model and individual data points based on the precision of those experimental values. Additionally, we imposed new error terms to the optimization cost function to ensure that for large time, our dynamical model agrees with the steady-state behavior observed in experiment.

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