Brian Strahl, Higher Education: The authoritative source of Brian Strahl’s personal information, links, and social activity.
Dr. Brian Strahl, associate professor of biochemistry & biophysics at UNC-Chapel Hill, is featured in a video and story about the history of epigenetics in the Jan 15, 2014 (Vol. 34, No. 2) issue of GEN (Genetic Engineering & Biotechnology News). The video and related featured story can be found here.
Drs. David Allis and Brian Strahl formally proposed the ‘histone code’ about 14 years ago. At that time, Dr. Strahl was a postdoctoral fellow in David Allis’ lab. This hypothesis provided an explanation for how distinct histone modifications, such as acetylation and methylation, could regulate epigenetic inheritance, gene expression and the control of cell growth and differentiation. However, limited experimental support exists for this hypothesis, and to date, it is unclear whether the binding of DNA-associated proteins to combinatorially-modified histones is a universal phenomenon of these regulators or is restricted to a subset of histone-binding proteins.
To address this long-standing question, Dr. Strahl’s lab is investigating how DNA-associated proteins bind to one or more histone modifications to regulate cellular function. With his colleagues, the Strahl lab has been utilizing high-density histone peptide microarrays to determine how proteins with specialized histone interaction domains associate with multiple histone modifications to regulate chromatin structure and function. Recent work has uncovered how the E3 ubiquitin ligase UHRF1 binds to histone H3 in a combinatorial manner – a binding event that governs the epigenetic inheritance of DNA methylation. To learn more, visit Brian Strahl’s page.
Providing researchers with high quality services for synthesis, purification, and characterization of synthetic peptides and preparation of custom designed peptide arrays. The core director is Dr. Krzysztof Krajewski, PhD; Faculty Director of the facility is Dr. Brian D Strahl, Associate Professor of Biochemistry & BIophysics at UNC Chapel HIll.
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UNC-CHAPEL HILL – DNA is often called the blueprint of life, but the four letter combinations that make up the genetic code are just part of the story. Built upon the DNA lies additional ‘epigenetic’ information in the form of a complex ensemble of chemical tags attached to the DNA itself and on proteins that package our DNA – called histones – which ultimately control how our genetic code is accessed and used. Interestingly, histones are decorated with many types of chemical tags, and their particular combinations have been referred to as the ‘histone code’. But understanding how this ‘code’ is interpreted by the cell has proven challenging due its sheer complexity and a lack of tools to study the ‘code’ inside the cell.
Now research from the University of North Carolina at Chapel Hill School of Medicine has shown how a protein called UHRF1 “reads” the ‘histone code’ in a specific way to perform an important cellular function. “Because the protein has been found to be defective in cancer, the finding not only lends new insight into functions downstream of the ‘histone code’ but could also point the way toward novel strategies for cancer treatment and prevention,” said senior study author Brian Strahl, PhD, associate professor of biochemistry and biophysics and member of the UNC Lineberger Comprehensive Cancer Center.
The research, which appears June 1st, 2013, in the journal Genes and Development, is the latest of many studies to investigate the ‘histone code’ hypothesized more than ten years ago by Strahl and his former postdoctoral advisor C. David Allis. The hypothesis suggests that distinct combinations of histone modifications work together to form a ‘code,’ akin to the classic genetic code, in which three-letter combinations of nucleotides make an amino acid. These histone modifications – chemical changes like phosphorylation, acetylation and methylation — generate an epigenetic language that is interpreted through the ability to recruit proteins to DNA and histones that in turn modulate cellular functions.
“This study provides important support for the ‘histone code’ hypothesis, and also reiterates how difficult it will be to crack this ‘code.’ It is not enough to understand how one tag works in isolation, we now have to look at all different combinations of tags on both histones and DNA to piece together the puzzle encrypting this second layer of information,” said Strahl.
Over the last decade, researchers have pinpointed a number of different “domains” that proteins use to interact with, or read, the ‘histone code’. Scott Rothbart, PhD, a postdoctoral research fellow in Strahl’s laboratory, previously showed that one such domain on the protein UHFR1 – called the tandem Tudor — helps it bind to a histone in the cell that is methylated at a specific place. Adjacent to the Tudor was another domain called a PHD finger that helped the protein also bind the unmodified end of a histone. Rothbart and Strahl wondered if these neighboring domains might function together to help UHRF1 to read the ‘histone code’ and, subsequently, influence its ability to function in the cell.
To investigate this question, the researchers used a highly sophisticated peptide microarray technology developed in the Strahl lab. Just as DNA microarrays contain sections of DNA sequence spotted on glass slides, these peptide arrays contained sections of modified histone proteins. When the researchers applied the UHRF1 protein to the array, they found it bound the histone differently when it contained the linked Tudor and PHD domains than when it contained the domains in isolation. They then used biochemical techniques to show that the two domains of UHRF1 functioned together in cells – whereby each domain is making a key contribution to promote binding to the histone protein in a specific way.
One of the main functions of UHRF1 is the maintenance of a critical modification known as DNA methylation. The researchers showed that when these domains of UHRF1 were not functioning together to read the ‘histone code’, DNA methylation patterns in the cell were eventually lost.
“Abnormalities in the patterning of DNA methylation are a hallmark of many cancers. In addition, UHRF1 has been found to be defective in a number of cancers including prostate, breast, kidney, and lung cancer,” said Scott Rothbart, PhD, who is lead author of the study.
“UHRF1’s function in maintaining DNA methylation seems to be reversible – if you take it out of the cell you lose DNA methylation, but if you add it back you restore DNA methylation. We therefore think that by using small molecules to disrupt the recognition of the ‘histone code’ by UHRF1, we may be able to reprogram DNA methylation patterns in cancer cells.”
The research was supported in part by the National Institutes of Health, the Carolina Partnership and the University Cancer Research Fund, the Natural Sciences and Engineering Research Council of Canada, and the American Cancer Society.
Study co-authors from UNC were Bradley M. Dickson, PhD, postdoctoral research associate; Krzysztof Krajewski, PhD, research assistant professor; and Dmitri B. Kireev, PhD, research professor. Other collaborators on the story were Cheryl Arrowsmith, PhD, professor; Michelle Ong, postdoctoral research associate; and Scott Houliston from the University of Toronto.
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Three scientists at the University of North Carolina (UNC) at Chapel Hill have received a $1 million grant from the W.M. Keck Foundation’s Medical Research Program to study a widespread but largely unexplored phenomenon that may be implicated in many diseases, including cancer.
The phenomenon, called protein methylation, has added a new dimension in our understanding of how genes and other aspects of the cell are regulated, explained Marcey L. Waters, principal investigator of the project and professor in the department of chemistry in UNC’s College of Arts and Sciences. Proteins are modified with these chemical tags, which in turn change their behavior in ways that are important for turning on or off their functions.
“However, protein methylation is challenging to study,” said Waters, “largely because we lack the right tools to study it. The goal of this grant is to help us develop the tools to better characterize this phenomenon – how many proteins are methylated in different cells, what happens when protein methylation goes awry, and how this influences other chemical interactions that regulate gene expression.”
The new tools will provide researchers with a map of these chemical tags and the patterns with which these tags decorate the surface of different proteins. A visual and/or chemical representation of these patterns may provide breakthrough insights into why certain cells become diseased while others stay healthy. Furthermore, Waters and her co-principal investigators, Drs. Brian D. Strahl and Xian Chen, associate professors in the department of biochemistry and biophysics in UNC’s School of Medicine, plan to use these new tools to pinpoint precisely which molecular interactions within cells break down and lead to disease. This could open the door to the development of highly specific and targeted therapies.
“Mapping differences in the protein methylation process in normal and diseased cells may provide key information for the development of future treatments,” said Waters.
Drs. Xian Chen and Brian Strahl are also members of the UNC Lineberger Comprehensive Cancer Center.
UNC Chapel Hill has established a High-Throughput Peptide Synthesis and Array Facility (HTPSA) to provide researchers with high quality consultation and peptide synthesis services including production, purification, and characterization of polypeptides and custom designed peptide arrays.
The facility is reasonably priced, fast and offers the highest possible quality and standards. We are experienced and can work with you to help design the right peptide(s) for your needs – whether it is a simple peptide for antibody production or a complex peptide design with multiple post-translational modifications. The facility can make peptide libraries as well as generate peptide arrays.
Typical peptides the faculty makes includes peptides containing nonstandard (modified or unnatural) amino acids, e.g. acetylated Lys, methylated Lys or Arg, phosphorylated Ser Thr or Tyr residues, fluorescent tags, biotinylation, D-amino acids, unnatural amino acids (e.g. 6-Cl-Trp), stable isotopes (2H, 13C, 15N) and PEG linkers/spacers. MAP peptides as well.
For more information, or for a quotation on a peptide or project, please contact us at the email below.
nature structural & molecular biology has selected a recent paper by UNC researcher Dr. Brian D Strahl as the November 2012 “article of the month.” In this paper, Dr. Strahl and colleagues show how UHRF1, an E3 ubiquitin ligase, links H3K9 methylation to DNA methylation maintenance in humans. nature structural & molecular biology has made this an open access article. The paper can be located using this link.
Garnering numerous awards for his professional accomplishments over the years, cancer researcher Dr. Brian D Strahl currently is an Associate Professor at the University of North Carolina (UNC) at Chapel Hill. At UNC, Dr. Strahl holds a faculty position in the Department of Biochemistry & Biophysics and is a member of the UNC Lineberger Comprehensive Cancer Center.
Brian Strahl’s research is centered on understanding how our DNA, which encodes the genetic blueprint of life, is packaged and properly accessed within cells. As it turns out, many cancers are caused by the inappropriate regulation of this packaging, which then leads to genes being turned “on” or “off” when they shouldn’t be. The information Dr. Strahl is learning will not only help to facilitate a greater understanding of cancer itself, but might pave the way for new treatments that could one day reduce cancer morbidity rates throughout the United States and around the world.
In addition to providing support to Dr. Strahl and his colleagues, the UNC Lineberger Comprehensive Cancer Center strives to improve cancer care services for the public through various educational and outreach initiatives. Promoting early detection as a primary means of increasing patient life expectancy, the Center aims to develop its clinical offerings continually, especially for medically underserved populations. To learn more about the UNC Lineberger Comprehensive Cancer Center, a National Cancer Institute (NCI) facility, visit www.unclineberger.org today.
In the new issue of Science Magazine (Vol. 338 no 6106 p549 October 26, 2012), science writer Jeffrey Perkel explores the recent Epigenomics roadmap initiative funded by the National Institutes of Health (NIH). In the article, Jeffrey interviews Dr. Brian D Strahl, Associate Professor at UNC Chapel Hill, about the grant he recently received from the roadmap initiative. Dr. Perkel describes how Dr. Strahl’s studies fit into the overall efforts of the epigenomics program, and he highlights how the new technologies and projects funded by this initiative have led to new fundamental insights into epigenetics and human health. To learn more, click on this link.
CHAPEL HILL, N.C. – Over the last two decades, scientists have come to understand that the genetic code held within DNA represents only part of the blueprint of life. The rest comes from specific patterns of chemical tags that overlay the DNA structure, determining how tightly the DNA is packaged and how accessible certain genes are to be switched on or off.
As researchers have uncovered more and more of these “epigenetic” tags, they have begun to wonder how they are all connected. Now, research from Brian D. Strahl's group at UNC has established a new link between two epigenetic modifications — histone H3 lysine 9 methylation and DNA methylation — in humans.
The study, which was published Sept. 30, 2012 by the journal Nature Structural & Molecular Biology, implicates a protein called UHRF1 in the maintenance of these epigenetic tags. Because the protein has been found to be defective in cancer, the finding could help scientists understand not only how microscopic chemical changes can ultimately affect the epigenetic landscape but also give clues to the underlying causes of disease and cancer.
“There’s always been the suspicion that regions marked by DNA methylation might be maintained by H3 lysine 9 methylation, and that has even been shown to be true in model organisms like fungus and plants,” said senior study author Brian D Strahl, PhD, associate professor of biochemistry and biophysics in the University of North Carolina School of Medicine and a member of UNC Lineberger Comprehensive Cancer Center. “But no one has been able to make that leap in human cells. It’s been controversial in terms of whether or not there’s really a connection. We have shown there is.”
Brian Strahl, along with his postdoctoral fellow Scott Rothbart, honed in on this discovery by using a highly sophisticated technique developed in his lab known as next generation peptide arrays. First the Strahl lab generated specific types of histone modifications and dotted them on tiny glass slides called “arrays.” They then used these “arrays” to see how histone modifications affected the docking of different proteins. One protein – UHRF1 – stood out because it bound a specific histone modification (lysine 9 methylation on histone H3) in cases where others could not.
Strahl and his colleagues focused the rest of their experiments on understanding the role of UHRF1 binding to this histone modification. They found that while other proteins that dock on this epigenetic tag are ejected during a specific phase of the cell cycle, mitosis, UHRF1 sticks around. Importantly, the protein’s association with histones throughout the cell cycle appears to be critical to maintaining another epigenetic tag called DNA methylation. The result was surprising because researchers had previously believed that the maintenance of DNA methylation occurred exclusively during a single step of the cell cycle called DNA replication.
“This role of UHRF1 outside of DNA replication is certainly unexpected, but I think it is just another way of making sure we don’t lose information about our epigenetic landscape,” said Strahl.
The research was funded by the National Institutes of Health and the North Carolina Biotechnology Center.
Study co-authors from UNC were Scott B. Rothbart, PhD, a postdoc in Brian D. Strahl’s lab at UNC; Krzysztof Krajewski, PhD, research assistant professor; and Jorge Y. Martinez, a former student in Strahl’s lab.
Media contact: Tom Hughes, (919) 966-6047, firstname.lastname@example.org
In a recent issue of Nature Methods (Vol. 9; pp 649-652), Editor Monya Baker examines the role of mass spectrometry in Chromatin Biology and Epigenetics research. In the article, titled “Mass spectrometry for chromatin biology”, Monya interviews Dr. Brian D. Strahl, Associate Professor at UNC Chapel Hill, on the role this important technology plays in identifying histone post-translational modifications and histone-associated proteins. To go to the article, click on this link.
In a recent issue of BioTechniques (Vol. 52, No. 3, March 2012, pp. 145–147), Editor Nathan Blow, Ph.D., examines the challenges of starting a research lab in the biomedical sciences. In one article titled “reflections on the modern lab”, Nathan interviews Dr. Brian Strahl, Associate Professor at UNC Chapel Hill, on the role technology and communication plays in running a research lab.