Dr. Brian David Strahl Awarded NIGMS Outstanding Investigator Grant

 

Brian David Strahl, Professor of Biochemistry & Biophysics and Oliver Smithies Investigator, has been awarded a 5-Year Outstanding Investigator R35 Maximizing Investigators’ Research Award (MIRA) for his research on gene expression and chromatin regulation. The goal of the MIRA award is to increase the efficiency of NIGMS funding by providing investigators with greater stability and flexibility to enhance scientific productivity and the chances for important breakthroughs.

Brian D. Strahl is a Professor & Vice-Chair of the Department of Biochemistry & Biophysics.

Brian David Strahl.jpg

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Yeh and Strahl named Smithies Investigators

The UNC School of Medicine selected professors from the departments of surgery, and biochemistry and biophysics for the annual award in honor of Oliver Smithies, UNC’s first Nobel Prize winner.

Yeh and Strahl named Smithies Investigators
Jen Jen Yeh, MD, and Brian Strahl, PhD

January 31, 2018

The UNC School of Medicine selected Jen Jen Yeh, MD, professor and vice chair of research for the department of surgery, and Brian Strahl, PhD, professor and vice chair of the department of biochemistry and biophysics, as Smithies Investigators, an annual award to honor senior faculty members who have made significant research contributions and achieved international recognition for their work. Both are members of the UNC Lineberger Comprehensive Cancer Center. Yeh has a joint appointment in the department of pharmacology.

The award was established in honor of the research achievements of UNC Nobel Prize Winner Oliver Smithies, DPhil, the Weatherspoon Eminent Distinguished Professor in the Department of Pathology and Laboratory Medicine.  The Smithies Investigators receive $75,000 for research over a five-year term, become members of the Oliver Smithies Society, and will present highlights of their research accomplishments at a special seminar in the fall.

Yeh was recruited to the UNC School of Medicine in 2005 and has been one of the most successful surgeon-scientists at UNC. She has an active surgical oncology practice focused on endocrine and pancreatic cancers. Her research lab focuses on identifying and studying novel therapeutic targets for the treatment of colorectal and pancreatic cancer. Recently her group identified new subtypes for pancreatic cancer, research that was published in Nature Genetics. Using her surgical expertise she also initiated a large Patient-Derived Xenograft Program with a major emphasis on the establishment of both primary and metastatic pancreatic tumors in order to use this platform for therapeutic and biomarker evaluation.

Yeh recently led the UNC Pancreas Specialized Program of Research Excellence (SPORE) submission and is a co-investigator on many NIH grants focused on topics as diverse as biostatistics and microfluidics. Her work has resulted in three patents, and she is well-recognized in her field of surgical oncology. Yeh has received multiple prestigious awards, including an American Surgical Foundation Research Fellowship, the Clinical Investigator Award from the Society of Surgical Oncology, and she was inducted into the American Society for Clinical Investigation, an honor society for physician-researchers.

Strahl is a leading researcher in his field and the faculty director of the UNC High-Throughput Peptide Synthesis and Array Facility. He started his lab at UNC in 2001, and it has been at the forefront of understanding how histones and their covalent modifications regulate chromatin structure and function, with a particular focus on how chromatin impacts gene regulation. His lab is also engaged in a high-throughput proteomics project involving histone peptide arrays to decipher how histone modifications – and the histone codes they generate – regulate the recruitment of chromatin-associated proteins that govern the diverse functions associated with DNA.

In addition to mentoring a large group of students, postdocs, and research staff, Strahl also co-founded a UNC start-up company called EpiCypher, which was selected as one of the two best start-ups by the US Congress in 2016. He is routinely invited to speak at universities for seminars, to attend major meetings and is a standing member on an NIH study section. He has received numerous awards and honors, including the Philip & Ruth Hettleman Prize, an NIH Eureka Award, and selection as a PEW Scholar.

Oliver Smithies, a faculty member at UNC for more than 25 years, won the Nobel Prize in Physiology or Medicine in 2007. He co-discovered a technique he called “gene-targeting,” which allows scientists to study genetic mutations by knocking out specific genes in mice. The method became ubiquitous in basic research labs and opened up a new kind of scientific inquiry into many different diseases.

Each year, the annual Oliver Smithies Nobel Symposium is hosted at the UNC School of Medicine.

Media Contact: Carleigh Gabryel, 919-864-0580, carleigh.gabryel@unchealth.unc.edu

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Researchers show how a cancer gene protects genome organization

UNC study uncovers crucial function of a yeast enzyme Set2 whose well-conserved human counterpart is often mutated in cancers, especially kidney cancer.

Media Contact: Mark Derewicz, 919-923-0959, mark.derewicz@unchealth.unc.edu

June 13, 2017

CHAPEL HILL, NC – UNC School of Medicine researchers have cracked a long-standing mystery about an important enzyme found in virtually all organisms other than bacteria. The basic science finding may have implications for understanding cancer development and how to halt it.

Researchers have known that the enzyme Set2 is important for transcribing genes – the process of making strands of RNA from the DNA. Transcription is critical for making proteins and other functional molecules. But Set2’s precise role in transcription hasn’t been clear. Now, UNC scientists discovered that the enzyme is particularly important for keeping transcription working properly when cells are under stress. Without Set2, cells that become stressed through the lack of nutrients begin mis-transcribing genes in a way that prevents cells from adapting properly to the stress.

“We think this solves a mystery about the purpose of Set2, and we now understand much better how gene transcription is prevented from happening at the wrong place and time,” said study senior author Brian Strahl, PhD, professor of biochemistry and biophysics and member of the UNC Lineberger Comprehensive Cancer Center.

Set2 enzymes in yeast and other lower organisms have close relatives in all animal species and plants. Its human cousin SETD2 is often found mutated in cancerous cells.

“These fundamental findings may help explain how SETD2 mutations could lead to inappropriate transcription within genes, which might then promote cancer initiation or progression,” Strahl said. His team’s research on SETD2 is ongoing.

The research, published in Cell Reports, involved collaboration between Strahl’s laboratory and that of Ian J. Davis, MD, PhD, associate professor of pediatrics and genetics at the UNC School of Medicine and member of the UNC Lineberger Comprehensive Cancer Center.

The discovery comes 15 years after the first studies of Set2 by Strahl and others, who found that the enzyme works by attaching molecules known as methyl groups to a support protein – or histone – around which DNA is spooled.

This methyl-attaching process is called methylation. Research has shown in recent years that the particular histone methylation performed by Set2 serves as a quality control check on gene transcription.

Transcription of a gene should start at a precise spot at the beginning of a gene and then continue until the end in order to fully transcribe the RNA. But in the absence of histone methylation laid down by Set2, transcription begins at the wrong places in the middle of a gene instead of at the beginning. If that is allowed to happen, the production of “cryptic” RNA transcripts can then interfere with the normal expression of a gene. The mis-expression of our genetic material can result in diseases such as cancer.

Strahl’s team thought Set2 might have something to do with these cryptic transcripts arising during stress. Previously, it was shown that Set2’s histone-methylating activity has the effect of attracting another enzyme to clear away chemical tags in the middle of a gene that, otherwise, can lead to inappropriate new transcription from within that gene.

“But under typical laboratory conditions, the deletion of Set2 and the subsequent increase in cryptic transcripts didn’t seem to harm cells very much,” Strahl said.

Strahl’s team then thought about cells under stress, which is what cells are like in disease states. His team conducted experiments to observe what happens in cells that don’t have Set2 when vital nutrients are removed. In this stressed state, cells normally activate a complex set of gene expression programs to help cope with the reduced nutrient resources.

“Nutrient depletion more accurately mimics what yeast cells experience in the wild,” Strahl said.

The scientists examined yeast cells that were deprived of nutrients, or were exposed to chemicals that reliably trigger the low-nutrient response. In these cells, not having Set2 proved to have major consequences.

“We found that this inappropriate transcription at the wrong place in genes exploded to high levels in stressed cells, and often interfered with the normal genes,” Strahl said. “As a result, the normal changes in genes that help cells survive under low-nutrient conditions did not happen correctly, and the cells became extremely sick.”

To Strahl and colleagues, the finding suggests that Set2 evolved to guard against harmful abnormal transcription in times of stress, when cells seem particularly vulnerable to this type of error. Why would cells be so vulnerable to cryptic transcription during the nutrient stress response? Strahl isn’t sure. But his team suspects that when there’s a sudden and widespread rearrangement of the molecular machinery of gene transcription, genes across the genome are left relatively open to inappropriate transcription.

“We found that a lot of the genes that show this crazy jump in cryptic transcription were not even related to the nutrient stress response,” Strahl said. “It’s as if there are genes throughout the genome that are just predisposed to this error, especially at this time when transcription is shifting dramatically.”

Strahl and Davis and their colleagues plan further research to determine why cryptic transcription rises so dramatically during nutrient stress. They also intend to find out whether Set2 is important for safeguarding transcription during other types of cellular stress.

In addition, the scientists are now studying Set2’s human counterpart, SETD2, which for unknown reasons is often mutated in tumor cells, especially in kidney cancers.

“It’s possible that SETD2 normally works as a major tumor suppressor by preventing inappropriate transcription,” Strahl said.

The lead author of the study was Stephen L. McDaniel, PhD, a former graduate student in the Strahl Laboratory. Other co-authors were Austin Hepperla, Jie Huang, Raghuvar Dronamraju, PhD, Alexander T. Adams, and Vidyadhar G. Kulkarni, PhD.Set2 illustration.jpg

(Illustration by Christ-claude Mowandza-ndinga)

 

 

 

The National Institutes of Health funded this work.

 

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New Strahl lab photo of 2017!

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New antibody portal bolsters biomedical research reliability

UNC’s Brian Strahl, PhD, and Van Andel Research Institute’s Scott Rothbart, PhD, create a robust online interactive database to address science’s ‘antibody crisis’.

July 23, 2015

CHAPEL HILL, NC – For years, a crisis has been brewing in molecular biology. The problem is that antibodies – research tools used to identify key proteins at work in a cell – aren’t always what they seem. Unreliable antibodies have led to numerous instances of false findings, failed experiments, and wasted money and samples.

Enter the Histone Antibody Specificity Database (www.histoneantibodies.com), a newly launched online portal that lets scientists find the right antibodies for their research with a much higher degree of confidence than ever before. Rather than relying on the claims of antibody manufacturers, the database is populated with validated test results, allowing researchers to access and compare real-world data and pick the most reliable antibody for each experiment.

A paper published today in the journal Molecular Cell describes the database and the science behind it.

“I can’t think of any field of biomedical research that doesn’t rely on antibodies; they’re typically the linchpin in many studies,” said Brian D. Strahl, PhD, professor of biochemistry and biophysics in the University of North Carolina School of Medicine and the study’s co-senior author. “But how reliable are these tools? There’s been a real awakening in the biological community that we need better ways to know if the antibodies are recognizing what they’re intended to recognize. That’s what we aim to accomplish with this portal.”

The web portal focuses on histone antibodies, a subset of antibodies that are central to the fast-growing field of epigenetics. Epigenetics researchers examine how layers of information outside the genome control the ‘on’ and ‘off’ state of genes, much like a light switch, that in turn affect all aspects of human health. Scientists use histone antibodies to track the roles of various proteins in this vital process of gene regulation.

“Epigenetic regulation of our genome is at the core of all aspects of biology, and basic research in this area is uncovering key mechanisms that contribute to human health and disease,” said Scott B. Rothbart, PhD, assistant professor in the Center for Epigenetics at Van Andel Research Institute (VARI) and co-corresponding author of the study. “Drugs targeting the epigenetic machinery are being tested in oncology clinics now, and a better understanding of what the antibodies are recognizing will help researchers define more precisely how epigenetics works and ultimately lead to better, stronger conclusions that can make a difference for drug discovery and future therapeutic interventions.”

Initially developed in the 1970s, laboratory-produced antibodies have been commercially available to scientists for decades. Since then, many researchers have simply ordered antibodies from among the hundreds of thousands on the market, taking their labels at face value. But a growing body of evidence has revealed that an alarming number of antibodies do not perform as advertised.

Each histone antibody is supposed to bind to a specific protein target, allowing scientists to track where and how that protein is being regulated in healthy and diseased cells. However, some antibodies have been observed binding to other proteins in addition to their primary target while other antibodies have been shown to bind to just one target, but not the target indicated on the product label. In some cases, an antibody’s accuracy and specificity vary from one lot to the next, suggesting quality-control issues in the manufacturing process.

All of these errors muddy – and in some cases, completely undermine – research results.

While some vendors have stepped up their testing and quality control efforts, others have not, and few researchers have the resources or time to do the battery of tests recommended to ensure their antibodies are performing as indicated.

The new database offers an easy way to access detailed information about the accuracy and specificity of more than 100 commonly used and commercially available histone antibodies.

The testing method used to populate the database is based on custom-designed peptide microarrays that Strahl and his colleagues developed. The arrays present a library of all of the chemical modifications or “tags” known to occur on histone proteins. Analyzing antibodies that are developed to target these different tags on the arrays quickly illuminates the types of tags to which each antibody is capable of binding. This matters a lot. Each tag is thought to have a different function. For example, turning a gene ‘on’ or ‘off’.

Once word got out about the team’s peptide array platform, Strahl and his colleagues started fielding calls from other scientists asking for advice on antibody selection. Such interest from the scientific community sparked the team’s idea to buy all of the most common histone antibodies, test them on the array, and publish the results in an online portal accessible to everyone.

“We wanted it to be much more than a simple search-and-go database,” Strahl said. “Peptide arrays like the ones we developed are now available commercially, so any researcher, antibody manufacturer, or pharmaceutical company can run these tests. We built the portal so that people can easily upload their own results and the database can continue to grow.”

The portal allows users to search for antibodies using multiple parameters. A quality-control plan is in place to ensure the validity of user-submitted data.

Strahl said he hoped the database would enable more accurate and reproducible epigenetic findings.

“You don’t expect every antibody to be 100% perfect, but we think it’s important for researchers to be able to know what the flaws are,” Strahl said. “That way, at least people can interpret their results with the right amount of caution based on what the antibodies see – or don’t see.”

This work was supported by grants from the NIH and the W.M. Keck Foundation

Additional UNC coauthors include Terry R. Magnuson, PhD, the Sarah Graham Kenan Professor and chair of the department of genetics in the UNC School of Medicine; Erin Shanle, PhD, a postdoctoral research associate in Strahl’s lab; Jesse R. Raab, PhD, a postdoctoral fellow in Magnuson’s lab; Krzysztof Krajewski, PhD, research assistant professor; and Angela H. Guo, an undergraduate researcher in Strahl’s lab. Other coauthors include Bradley M. Dickson, PhD, a computational biophysicist in Rothbart’s lab at VARI, graduate student Adrian T. Grzbowski and Alexander J. Ruthenburg, PhD, of the University of Chicago; Steven Z. Josefowicz, PhD, and David Allis, PhD, of The Rockefeller University; and Stephen M. Fuchs, PhD, of Tufts University.

Van Andel Institute (VAI) is an independent biomedical research and science education organization committed to improving the health and enhancing the lives of current and future generations. Established by Jay and Betty Van Andel in 1996 in Grand Rapids, Michigan, VAI has grown into a premier research and educational institution that supports the work of more than 270 scientists, educators and staff. Van Andel Research Institute (VARI), VAI’s research division, is dedicated to determining the epigenetic, genetic, molecular, and cellular origins of cancer, Parkinson’s, and other diseases, and translating those findings into effective therapies. The Institute’s scientists work in on-site laboratories and participate in collaborative partnerships that span the globe. Learn more about Van Andel Institute or donate by visiting www.vai.org. 100% To Research, Discovery & Hope®

Media contacts: Mark Derewicz, UNC School of Medicine, 919-923-0959, mark.derewicz@unch.unc.edu; Beth Hinshaw Hall, Van Andel Research Institute, 616-234-5519, beth.hinshawhall@vai.org

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UNC Program in Chromatin and Epigenetics Launches

UNC has launched a new program that aims to address the fundamental gaps in knowledge surrounding epigenetic regulation, with a long-term goal of developing novel therapeutic approaches towards treating human disease. The program is centered around a highly collaborative and team science environment that has a dedicated goal of solving fundamental and challenging problems in chromatin biology – with an emphasis on developing novel approaches towards treating human disease. The large number of research faculty at UNC specializing in different areas of epigenetic research are optimally positioned to meet this challenge.

Faculty at UNC are focused on the basic mechanisms of epigenetic regulation using a variety of model organisms, high-throughput drug discovery efforts to target epigenetic machinery and clinical research that emphasizes epigenetic translational science employing the knowledge gained by basic research and drug discovery efforts. These researchers employ a range of cutting edge technologies, such as genomic and proteomic techniques, to address a vast number of epigenetic problems – and this research is supported by top-notch core facilities. The Chromatin and Epigenetics Program currently encompasses 34 faculty members, and participation of several laboratories from the National Institute of Environmental Health.

Along with the many resources and events associated with this new program, a highlight is the Chromatin and Epigenetics Certificate Program. Doctoral students interested in being formally part of the Program in Chromatin and Epigenetics can apply for entrance into a certificate program. The goal of this program is to provide students with more emphasis on epigenetic mechanisms and further exposure to approaches and techniques used in epigenetic research.

The leadership behind the program are Terry Magnuson, PhD, and Brian Strahl, PhD. Magnuson is a professor and chair of Genetics at UNC and the Executive Associate Dean for Research for the School of Medicine. Work in the Magnuson lab focuses on the role of mammalian genes in unique epigenetic phenomena such as genomic imprinting, X-chromosome inactivation, stem cell pluripotency and the tumor suppressor role of chromatin remodeling complexes. Strahl is a professor and director of graduate studies of Biochemistry and Biophysics at UNC. The Strahl lab addresses how histone post-translational modifications, and the combinatorial codes they create, contribute to the structure and function of chromatin.

sample epi Image

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Epigenetic Breakthrough: A first of its kind tool to study the histone code

Scientists from UNC-Chapel Hill have created a new way to investigate epigenetic mechanisms important in diseases ranging from Alzheimer’s to cancers.

Robert Duronio, PhD; Daniel McKay, PhD; Greg Matera, PhD; Brian Strahl, PhD.

CHAPEL HILL, NC –University of North Carolina scientists have created a new research tool, based on the fruit fly, to help crack the histone code.  This research tool can be used to better understand the function of histone proteins, which play critical roles in the regulation of gene expression in animals and plants.

This work, published in the journal Developmental Cell, opens the door to experiments that are expected to uncover new biology important for a host of conditions, such as neurological diseases, diabetes, obesity, and especially cancer, which has become a hotbed of epigenetic research.

“People think cancer is a disease of uncontrolled proliferation, but that’s just one aspect of it,” said Robert Duronio, PhD, professor of biology and genetics and co-senior author. “Cancer is actually a disease of development in which the cells don’t maintain their proper functions; they don’t do what they’re supposed to be doing.” Somehow, the gene regulation responsible for proper cell development goes awry.

One aspect of gene regulation involves enzymes placing chemical tags or modifications on histone proteins – which control a cell’s access to the DNA sequences that make up a gene. Properly regulated access allows cells to develop, function, and proliferate normally. The chemical modification of histones is thought to be a form of epigenetic information – information separate from our DNA – that controls gene regulation. This idea is based on the study of the enzymes that chemically modify histones. However, there is a flaw in this argument.

“In complex organisms, such as fruit flies, mice, and humans, scientists have only been able to infer how these enzymes mechanistically accomplish their tasks,” said Daniel McKay, PhD, assistant professor of genetics and biology and first author of the paper. “It’s been technically impossible to directly study the role of histone modifications. Now, through our collaboration between UNC biologists, we’ve been able to develop a tool in fruit flies to directly test the function of histones independently of the enzymes that modify them.”

This is crucial because therapies, such as cancer drugs, can target histones. With this new research tool, scientists will be able to better study thousands of enzyme-histone interactions important for human health.

“If you think of the genome as a recipe book, then you could say we’ve made it possible to know that there are hidden ingredients that help explain how specific recipes turn out correctly or not,” said Greg Matera, PhD, professor of biology and genetics and co-senior author of the paper.  “That’s the first step in scientific discovery – knowing that there are things we need to look for and then searching for them.”

Beyond Yeast

Before now, a lot of this epigenetic research had been done in yeast – single cell organisms that also use enzymes to lay chemical tags on histone proteins. This work has yielded many interesting findings and has led to the development of therapeutics. But some of this work has led to an oversimplification of human biology, leaving many questions about human health unanswered.

For instance, in complex organisms, enzymes in cells typically do more than one thing. One likely reason for this is that animals undergo cellular differentiation; human life begins as a single cell that differentiates into the various cell types needed for different organs, body parts, blood, the immune system, etc. This differentiation has to be maintained throughout life.

“Because of this, animals likely have a greater requirement for epigenetic regulation than yeast do,” Matera said. “Animal cells have to ‘remember’ that they must express genes in specific ways.” When cancer cells start dividing rapidly to form tumors, these cells are actually reverting to an earlier time in their development when they were supposed to divide rapidly. The gene regulation that was supposed to rein them in has gone haywire.

Whereas in yeast, a histone-modifying enzyme might have a single regulatory task, the human version of that same enzyme might have other regulatory tasks that involve additional proteins.

“In fact, maybe the really critical target of that one modifying enzyme is some other protein that we don’t know about yet,” Matera said. “And we need to know about it.”

The best way to figure that out would be to make it impossible for the enzyme to modify a histone by changing – or mutating – the histone protein. If a histone protein could be disabled in this way and cells still behaved normally, then that would mean there was some other protein that the enzyme acted on. To do this, however, would require replacing a histone gene with a genetically engineered one that could not be modified by an enzyme.

The problem is that in animals, such as mice and humans, there are many histone genes and they are scattered throughout the genome. This makes replacing them with ‘designer’ histone genes difficult.  In addition, other genes are located in between the histone genes. Therefore, deleting the portion of the chromosome with histone genes in order to replace them with a modified one would wind up deleting other genes vital for survival. This would make such an approach in, say, a mouse, useless.

“It has been technically impossible to do this kind of research in complex organisms,” Duronio said. “But fruit flies have all their histone genes in one place on the chromosome; this makes it feasible to delete the normal genes and replace them with designer genes.”

Designer genes

Matera, Duronio, and McKay led an effort to delete the histone genes in fruit flies and replace them with specific designer histone genes they created. These new genes were created so they could not be the repositories of epigenetic tags or modifications. That is, the modifying enzyme would not be able to do its job on that particular protein.

As shown in the Developmental Cell paper, the researchers put their new tool to the test. They “broke” one histone protein that had been identified to interact in a specific way with a modifying enzyme, and they got the outcome in fruit flies they expected. But for another enzyme-histone interaction, the researchers got an unexpected result.

Previously, in mammalian cells, other researchers had discovered that when you mutate a specific modifying enzyme, the result is death because the cells can’t replicate.

With their new fruit fly research model, the UNC researchers altered the histone gene so that this particular enzyme could not modify its histone protein target. The result was not death. In fact, the flies lived and flew as normal flies do. This meant that the enzyme, which was previously proven to be vital to life, must do something else very important.

“There must be another target for that modifying enzyme,” Matera said. “There must be another hidden carrier of epigenetic information that we don’t know about.”

McKay added, “This is a demonstration of the potential of our epigenetic platform. Going forward, we’re going to do a lot more experiments to identify more discrepancies and hopefully other targets of these enzymes. We’re on the ground floor of a long-term project.”

This research shows that the epigenetic recipe book for yeast is thin. The recipe book for humans, which is genetically akin to the one for fruit flies, is much thicker, more complex, and full of hidden ingredients scientists have yet to discover.

Now, scientists have a tool to test the recipes.

Brian Strahl, PhD, professor of biochemistry and Biophysics in the School of Medicine, is also a principal investigator of this study.

Duronio, Matera, and McKay are professors in the UNC School of Medicine and the College of Arts and Sciences.

Strahl, Duronio, and Matera are members of the UNC Lineberger Comprehensive Cancer center. Matera, Duronio, and McKay are members of the Integrative Program for Biological and Genome Sciences. Duronio is the director of the program.

National Institutes of Health and the University of North Carolina funded this research.

Media Contact: Mark Derewicz, 919-923-0959, mark.derewicz@unchealth.unc.edu

February 9, 2015

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