Researchers in the Common Fund’s Epigenomics program have discovered a hidden layer of meaning contained within genes. Dr. John Stamatoyannopoulos at the University of Washington, along with his colleagues, have discovered some regions of DNA serve a double purpose. These regions contain instructions for how to make a protein, as well as information about when and how much of the protein should be made. Scientists previously thought that a particular stretch of DNA could be part of the genetic code, specifying the sequence of amino acid “building blocks” used to make a protein, or part of the regulatory code, containing elements that control expression of the protein. Dr. Stamatoyannopoulos and colleagues have identified “duons,” stretches of DNA within the genetic coding regions that also contain a regulatory sequence called a transcription factor binding site. The researchers created a map showing where transcription factors were bound within genetic coding regions. Looking across 81 diverse human cell types, they found that approximately 15 percent of DNA within genetic coding regions has this dual purpose. This study suggests that mutations within these duons could alter the protein sequence itself, the regulation of the protein, or possibly both simultaneously. These results have important implications for how researchers interpret genetic mutations to provide information about human health and disease.
Stergachis AB, Haugen E, Shafer A, Fu W, Vernot B, Reynolds A, Raubitschek A, Ziegler S, LeProust EM, Akey JM, Stamatoyannopoulos JA. Exonic Transcription Factor Binding Directs Codon Choice and Affects Protein Evolution. Science, Dec. 13, 2013; 342; 1367-1372. PMID: 24337295.
Read the University of Washington press release here.
Read more about the Epigenomics program here.
DNA is perceived to be a stable “blueprint” molecule since it encodes the proteins that function within a cell and also passes genetic information through the generations. However, DNA is actually extremely dynamic in many ways. Just one example of how DNA can be altered in surprising ways is by transposable elements (TEs), also called “jumping genes.” TEs, which make up approximately half the human genome, are sequences of DNA that move from one location in the genome to another. Scientists previously thought that TEs were silenced in the human genome, tagged with epigenetic marks to ensure that TEs are locked in place and prevented from disrupting the normal functions of the genome. It has recently become appreciated that in some cases, TEs play important roles in regulating gene expression. However, it is not well understood how this occurs or how widespread this phenomenon is.
Drs. Ting Wang and Joseph Costello, supported by the Epigenomics program, along with their colleagues, identified epigenetic signatures marking regions of TEs that act as enhancers, regions of DNA that play a role in promoting gene expression. Intriguingly, the epigenetic signatures marking enhancer regions of TEs occur in a tissue-specific manner, and can be used to distinguish different tissues or possibly even cell types within tissues. The researchers also showed that these tissue-specific TE enhancer regions can influence expression of genes known to play important roles in the relevant tissue. For example, a TE region with an epigenomic signature for brain cells, but not immune cells, was found to influence expression of a gene involved in communication between brain cells, and did not influence expression of a gene involved in immune system responses. This research suggests that TEs may play a much more wide-spread role in tissue-specific gene regulation than was previously thought, and highlights the importance of including TEs in models of genetic and epigenetic regulation.
Read more about the Epigenomics program here.
This research also used data from the ENCODE (ENCyclopedia Of DNA Elements) project at the National Human Genome Research Institute (NHGRI). Read more about ENCODE here.
Xie M, Hong C, Zhang B, Lowdon RF, Xing X, Li D, Zhou X, Lee HJ, Maire CL, Ligon KL, Gascard P, Sigaroudinia M, Tlsty TD, Kadlecek T, Weiss A, O’Geen H, Farnham JP, Madden PA, Mungall AJ, Tam A, Kamoh B, Cho S, Moore R, Hirst M, Marra MA, Costello JF, Wang T. DNA hypomethylation within specific transposable elements families associates with tissue-specific enhancer landscape. Nature Genetics, 2013, Jul; 45(7): 836-41. PMID: 23708189.
More effective therapeutics are needed for numerous conditions affecting people, yet drug development remains inefficient. Investigators supported by the Common Fund Library of Integrated Network-based Cellular Signatures (LINCS) program have discovered new insights into the pharmacological properties of drugs that should help us design better therapeutics and more accurately predict their effects. While most studies of drug effects focus on measures of drug potency, e.g., by emphasizing the dose needed to experimentally reduce cell numbers in half, Fallahi-Sichani and colleagues at Harvard Medical School and the Oregon Health and Science University found that other measures of the response of cells to drugs can provide additional insights. They found that different measures are more informative at different doses of the drug response, e.g., some are more informative at higher doses and some at lower doses. They also found that the different measures do not always correlate with each other, e.g., when compared across different drugs or different cell types. Yet some measures correlate with cell type and others with drug class. In addition, the different measures each reveal unique information that contributes insights into the action of the drug. The findings indicate that it is worthwhile to compare multiple parameters when examining the variability of drug effects, and expand the way we should think about parameters of drug activity. In some cases the underlying explanation comes from how individual cells might behave differently from a population of cells.
Fallahi-Sichani M, Honarnejad S, Heiser LM, Gray JW, Sorger PK. Metrics other than potency reveal systematic variation in responses to cancer drugs. Nat Chem Biol. 2013 Sep 8. PMID 24013279.
Using PROMIS measures to evaluate patients’ recall of sexual function and activity reveals mood as a critical biasing factor
The NIH Common Fund Patient-Reported Outcome Measurement Information System® (PROMIS®) program aims to use patient-reported data to change the way clinical information is collected, utilized, and reported. For patients to be able to accurately report their symptoms and health-related quality of life to physicians and other care givers, measures must ask questions that are comprehensible and convey meaning to the patient while not burdening them with too many questions. If such patient reported measures are successfully developed and validated, they have the potential to improve clinical care. One important measure relates to overall sexual health and function, something that is hindered by numerous chronic diseases and conditions as well as their treatments. A new study led by PROMIS investigators at Duke University Medical Center has illustrated that people can remember their sexual function and activity over the previous month reasonably well, but their gender and the mood they feel at the time of reporting can influence what they report. They showed that while both genders overestimated interest in sexual function, males did so to a greater extent. The authors suggest that recall in this capacity could be affected by underlying gender stereotypes. Another major factor directly related to both over- and under-reporting was mood. If the patients were in a positive mood they tended to over-report and if they were in a negative mood they would generally under-report sexual interest. These findings indicate that physicians should consider the mood of their patients’ when administering the questionnaire. The findings from this study may lead to improved methods for accurately determining sexual health and activity, a critical factor in patients’ intimate relationships.
Read the Duke University Medical Center Press Release here
Weinfurt KP, Lin L, Dombeck CB, Broderick JE, Snyder DC, Williams MS, Fawzy MR, Flynn KE. Accuracy of 30-Day Recall for Components of Sexual Function and the Moderating Effects of Gender and Mood. J Sex Med. Jun 26, 2013. PMID: 23802907.
Most cells in the human body contain the same DNA, yet different types of cells have vastly different shapes, sizes, and functions. How do these differences arise? Chemical modifications to DNA and DNA-associated proteins, called epigenetic modifications, help instruct a cell to express only a sub-set of genes, giving rise to different characteristics for different cell types. Epigenetic regulation of gene expression changes during development, and can also change as a result of environmental exposures, pharmaceuticals, aging, and diet. Some epigenetic changes promote health and normal development, while others may contribute to a variety of diseases. Three recent publications in the journal Cell from the Epigenomics program’s Reference Epigenome Mapping Centers reveal important insights about epigenomic changes that take place during development, as non-specialized stem cells differentiate into specific cell types, such as heart, brain, skin, and many more.
Dr. Bing Ren at the San Diego Epigenome Center examined epigenetic events that occur during early embryonic development, as stem cells begin to differentiate into specific cell lineages. Dr. Ren’s work shows that distinct epigenetic mechanisms regulate early and late stages of stem cell differentiation. Interestingly, several gene families that are known to play important roles in development were notably lacking in one type of epigenetic mark, called DNA methylation, in early stages of development. Some of these same genes were found to have excess levels of DNA methylation in cancer, suggesting a possible role for epigenetic regulation of developmental genes in several types of cancer.
An additional study by Drs. Bradley Bernstein and Alexander Meissner, from the Reference Epigenome Mapping Center at the Broad Institute, examined epigenomic changes that occur as human embryonic stem cells differentiate into the three germ layers that develop in an embryo: ectoderm (which becomes epidermis, nervous system, eyes, and ears), mesoderm (which becomes muscle, bone, cartilage, the circulatory system, and the urogenital system), and endoderm (which becomes parts of the gastrointestinal tract, the liver, the pancreas, and the lungs). This study revealed several discrete events that occur during differentiation into each germ layer, providing new insight into how human germ layers are specified during development. Additionally, this information may prove useful to scientists who seek to differentiate induced pluripotent stem cells (iPSCs) for the purpose of repairing or replacing a wide range of tissues damaged by disease or injury.
In a separate study, Drs. Bernstein and Meissner, along with colleagues across the Epigenomics Mapping Consortium, systematically mapped global changes in chromatin, the physical structure of DNA and proteins inside a cell. The conformation of chromatin is regulated by epigenetic factors, leading to changes in gene expression (see “A Scientific Illustration of How Epigenetic Mechanisms Can Affect Health”). By generating over 300 chromatin state maps from diverse human tissues and stem cells, the researchers have discovered signature patterns of “active” chromatin, representing genes that are being expressed, versus “repressed” chromatin, representing genes that are not expressed. During development, chromatin changes from a largely accessible state to a more restrictive state. The chromatin state maps reveal that cells of different developmental stages, or exposed to different environmental conditions, can be distinguished by characteristic differences in chromatin state maps. Prior to this study, much of what scientists knew about chromatin states came from studying cell lines derived from various model organisms.
Collectively, these studies provide a wealth of information about epigenetic dynamics in human cells within different tissues, during various developmental stages, and under a variety of environmental conditions. The extensive data sets available in these publications will be a valuable resource for researchers in a wide range of biomedical fields.
Read more about the Epigenomics program here.
From Dr. Bing Ren:
Xie W, Schultz MD, Lister R, Hou Z, Rajagopal N, et al. Epigenomic Analysis of Multi-lineage Differentiation of Human Embryonic Stem Cells. Cell, 2013 May 7; http://dx.doi.org/10.1016/j.cell.2013.04.022 . PMID: 23664764.
From Drs. Bernstein and Meissner:
Gifford CA, Ziller MJ, Gu H, Trapnell C, Donaghev J, et al. Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells. Cell, 2013 May 7; http://dx.doi.org/10.1016/j.cell.2013.04.037 . PMID: 23664763.
Zhu J, Adli M, Zou JY, Verstappen G, Coyne M, et al. Genome-wide Chromatin State Transitions Associated with Developmental and Environmental Cues. Cell, 2013 Jan 31; 152(3): 1-13. PMID: 23333102.
Common Fund Supported Investigators Honored by Election to prestigious science academy
Each year, the National Academy of Sciences elects new members in recognition of their distinguished and continuing achievements in original research. Becoming elected as a member of the Academy is regarded as one of the highest honors that a scientist can receive for their academic accomplishments. In 2013, the academy elected a total of 84 new members in conjunction with its 150th annual meeting. Of this select cohort, eight have received funds from the NIH Common Fund to pursue highly innovative biomedical research. Each of these eight senior investigators contributed valuable research with potential for accelerating human health. The newly elected members to the academy who were supported in part through the Common Fund are:
- Barres, Ben A.; professor and chair, department of neurobiology, Stanford University School of Medicine, Stanford, Calif.
- Boeke, Jef D.; professor of molecular biology and genetics, department of molecular biology and genetics, Johns Hopkins University School of Medicine, Baltimore
- Quake, Stephen R.; investigator, Howard Hughes Medical Institute, professor, departments of bioengineering and of applied physics, Stanford University, Stanford, Calif.
- Breaker, Ronald R.; investigator, Howard Hughes Medical Institute, and Henry Ford II Professor, department of molecular, cellular, and developmental biology, Yale University, New Haven, Conn.
- Singer, Robert H.; co-director, Gruss Lipper Biophotonics Center, and professor and co-chair, department of anatomy and structural biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y.
- Turrigiano, Gina; professor, department of biology, Brandeis University, Waltham, Mass.
- Wagner, Gerhard; Elkan Rogers Blout Professor of Biological Chemistry and Molecular Pharmacology, department of biological chemistry and molecular pharmacology, Harvard Medical School, Boston
- Willard, Huntington F.; Nanaline H. Duke Professor of Genome Sciences and director, Institute for Genome Sciences and Policy, Duke University, Durham, N.C.
New Innovator Harald C. Ott and his colleagues at Massachusetts General Hospital (MGH) have developed a new method to bioengineer kidneys that could someday enable scientists to generate and transplant patient-specific bioengineered organs into patients. Kidneys play a critical role in the maintenance of homeostasis in the body by filtering waste and excess fluid from the blood. There are approximately one million patients in the U.S. with kidney failure, or end-stage renal disease (ESRD); the only possible cure is kidney transplantation. Currently, the waitlist for kidney transplants in the U.S. is more than three years long. Even with successful transplantation there is a high risk for transplant rejection or loss of transplant function over time.
The scientists from MGH were able to remove cells from cadaver kidneys, not normally suitable for transplantation, to create a cell-free kidney scaffold that maintained the protein structure and composition of normal functioning kidneys. Once the host cells were removed, the researchers used human umbilical vein cells and neonate mice kidney cells to repopulate the kidney. Following an incubation that mimics the human body environment, the researchers showed that the patient-specific kidneys had restored function and were able to reabsorb electrolytes and sugars, and produce urine both in the laboratory and in kidneys they transplanted into rats. These bioengineered kidneys could potentially address two major issues currently challenging kidney transplantations. First, they provide the initial steps towards developing kidneys in the lab that can be transplanted into patients, effectively reducing the wait time for critical ESRD patients. Second, developing the technology to repopulate bioengineered kidneys with patient-specific cells could result in a reduction in the risk of kidney rejection after transplantation. While these bioengineered kidneys still need to be developed further before they become a fully implantable treatment option in human patients, this new technology can be applied to other organs, and is leading the way toward organ bioengineering.
- Watch Dr. Ott describe this work on the NatureVideoChannel here
- Read the MGH News Release here
- Read more about the NIH Director’s New Innovator Award Program here.
Song JJ, Guyette JP, Gilpin SE, Gonzalez G, Vacanti JP, Ott HC. Regeneration and Experimental Ortotopic Transplantation of a Bioengineered Kidney. Nature Medicine, April 14, 2012. DOI: 10.1038/nm.3154.
A major challenge to researchers studying the brain has been the inability to study a fully intact brain, from both the global and microscopic perspectives. For example, researchers might want to examine the way a chemical interacts with brain cells, or neurons, both in the context individual neurons and of long neural circuits across the entire brain. Previously, researchers had to choose either to study a fully intact brain, which involves a lengthy sample preparation process and potential structural dissimilarities compared to the original organ, or to study small sections of the brain where one can examine fine molecular and cellular interactions without knowledge of the original complex structure of the neural circuit and structure of the intact brain. Dr. Karl Deisseroth, a 2012 Transformative Research Awardee from Stanford University and his colleagues, have combined tools from the fields of chemical engineering, computational optics, and molecular genetics to develop a new technology to solve this problem by transforming a fully intact mouse brain into a completely clear gel-based brain with all structural and molecular integrity intact. This new technology, named Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue hYdrogel (CLARITY) replaces lipids, or fats, which make the brain appear white outside of the body, and help form the structural basis for the brain, with a clear gel-like material that binds to cells, proteins, DNA, RNA, and other small molecules in the brain. The result is a completely clear brain with a gel-like consistency that maintains the same molecular and cellular relationships and structure as the original brain.
The new process, allows researchers to fluorescently tag small molecules and specific cell types to visualize individual molecular interactions as well as entire cellular networks in 3-D providing insight at both the molecular and whole system level which previously was not possible. CLARITY can be used by researchers to observe fine details of brains from animals and human patients with symptomatic neurological diseases without losing the larger-scale whole system perspective, potentially leading to new insights into diseases that affect the brain.
- Read more about this exciting new technology and watch videos of mouse brains transformed using CLARITY in the NIH Press Release here
- Read about this exciting new technology in the NIH Director’s Blog here
- Read the New York Times Article here
Chung K, Wallace J, Kim S-Y, Kalyanasundaram S, Andalman AS, Davidson TJ, Mirzabekov JJ, Zalocusky KA, Mattis J, Denisin AK, Pak S, Bernstein H, Ramakrishnan C, Grosenick L, Gradinaru V, Deisseroth K. Structural and molecular interrogation of intact biological systems. Nature, April 10, 2012. DOI: 10.1038/Nature12107.
A team of scientists at the Oak Ridge National Laboratory (ORNL) funded by the NIH Common Fund Human Microbiome Project (HMP) have made new discoveries about a microbe that is important in human oral health. Using cutting-edge technology, the team was able to complete full sequencing of the genome from a single cell. The ability to isolate just a single bacterial cell and sequence the genome is an important component of examining the human microbiome because it allows for the study of species that cannot be cultured in the lab. The organism the examined is most closely related to sulfate reducers, which are normally found in salt marshes, sewer pipes, hot springs, and surprisingly the human mouth. Studies have shown that this type of bacteria is elevated in patients suffering from periodontitis, a disease marked by swelling and infection of areas that support our teeth. New findings presented in the current study show that this species uses a unique coding scheme that likely allows it to successfully compete in the complex oral microbial environment. The technology advancement and scientific findings reported in this study will increase our understanding of the role that our microbes play in oral health.
Campbell JH, O'Donoghue P, Campbell AG, Schwientek P, Sczyrba A, Woyke T, Söll D, Podar M. UGA is an additional glycine codon in uncultured SR1 bacteria from the human microbiota. Proc Natl Acad Sci USA 2013, Mar 18. PMID: 23509275.
More than 60,000 patients in the United States undergo general anesthesia for surgery every day. Currently, doctors use indirect measures of the brain state, such as heart rate and blood pressure, along with drug pharmacokinetics, pharmacodynamics and exhaled anesthetic gas typically are converted to a simple index score to indicate if a patient is adequately anesthetized during surgery. These indices are neither entirely reliable nor very informative. Inadequately administered anesthesia can result in intraoperative awareness and post-operative delirium. Drs. Emery N. Brown and Patrick L. Purdon, former NIH Director’s Pioneer Awardee and current NIH Director’s New Innovator Awardee, respectively, have studied brain activity during propofol-induced anesthesia using electroencephalogram (EEG) technology, which measures scalp electrical potentials, to better understand the mechanism of unconsciousness and to establish a direct method of tracking the transition between consciousness and unconsciousness during general anesthesia. In this study, the researchers gradually administered and reduced the anesthesia drug propofol in patients, while monitoring brain activity and behavioral loss of consciousness by asking patients to respond to auditory stimuli. This gradual induction and emergence from anesthesia allowed the researchers to precisely define an EEG brain signature, as well as behavioral markers that are associated with consciousness, unconsciousness, and the transition between these two states in patients undergoing propofol-induced general anesthesia. This research has provided a deeper understanding of the mechanism of propofol-induced loss of consciousness, and could be used to determine the EEG brain signatures of other anesthetics. Additionally, these results could be used to develop more direct and reliable methods for monitoring brain states of patients undergoing general anesthesia and could lead to new insights into the tailoring of drug dosage in real-time.
P. L. Purdon et al., Electroencephalogram signatures of loss and recovery of consciousness from propofol. Proceedings of the National Academy of Sciences, (March 4, 2013, 2013).
New approach to attacking viruses: Researchers discover effective inhibitor to control herpesvirus infection and reactivation
Members of the herpesvirus family establish life-long dormant infections in people that can reactivate at any time to cause disease. Presently, there has been a focus on treatments that target the late stages of infection in those with herpes, particularly simplex virus (HSV) types 1 and 2, which cause oral and genital herpes. Furthermore, serious illness occurs when immune-compromised patients previously infected with another type of herepesvirus, human cytomegalovirus (CMV) suffer a reactivation. To date, drugs have been developed to target late stages of infection, with some success. In a new study, a probe developed from the NIH Chemical Genomics Center (NCGC), which is funded by the NIH Common Fund Molecular Libraries program, has been shown to be effective during lab studies at repressing early expression genes and therefore preventing infections from establishing. This molecule works by targeting human proteins to fight infections. Their studies also demonstrate that reactivation can be inhibited by the probe compound. Overall, there are implications for the prevention of infections as well as long-term treatment in infected patient to prevent reactivation episodes. This new area of research is beginning to show results for a number of viral diseases.
Read more about this research advance here.
Liang Y, Vogel JL, Arbuckle JH, Rai G, Jadhav A, Simeonov A, Maloney DJ, Kristie TM. Targeting the JMJD2 Histone Demethylases to Epigenetically Control Herpesvirus Infection and Reactivation from Latency. Sci Transl Med. 2013 Jan 9. PMID: 23303604.
Three NIH Common Fund Awardees, Drs. Titia de Lange, Eric S. Lander, and Lewis C. Cantley, were selected as inaugural winners of the Breakthrough Prize administered by the Breakthrough Prize in Life Sciences Foundation. The Breakthrough Prize in Life Sciences Foundation is a non-profit corporation, founded by technology innovators, Sergey Brin and Anne Wojcicki, Mark Zuckerberg and Priscilla Chan, and Yuri Milner, developed with the goal of “advancing breakthrough research, celebrating scientists and generating excitement about the pursuit of science as a career.” Prizes are awarded based on past achievement, and in addition to the distinction of the being an awardee, winners receive three-million dollars to inspire more freedom and opportunity to pursue groundbreaking research.
Dr. Titia de Lange, a 2005 NIH Director’s Pioneer Award recipient, and Leon Hess Professor at the Rockefeller University, was selected for her trailblazing work on telomeres, illuminating how they protect chromosome ends and their role in genome instability in cancer. Drs. Lander and Cantley both received funds through the NIH Common Fund Molecular Libraries program. Dr. Lander, President and Founding Director of the Broad Institute of Harvard and MIT and Professor of Biology at MIT, was selected for the discovery of general principles for identifying human disease genes, and enabling their application to medicine. Dr. Cantley, Margaret and Herman Sokol Professor and Director of the Cancer Center at Weill Cornell Medical College and New York Presbyterian Hospital was awarded the prize for the discovery of PI 3-Kinase and its role in cancer metabolism.
Read more about NIH-funded scientists in the inaugural class of laureates on the NIH Director’s Blog here.
Read more about the Breakthrough Prize in Life Sciences Foundation, the Breakthrough Prize in Life Sciences Award, and the eleven inaugural awardees here.