Center for Genes

Denver, CO, United States

Center for Genes

Denver, CO, United States
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Sasse S.K.,National Jewish Health | Kadiyala V.,National Jewish Health | Danhorn T.,Center for Genes | Panettieri R.A.,Rutgers University | And 3 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2017

Glucocorticoids exert important therapeutic effects on airway smooth muscle (ASM), yet few direct targets of glucocorticoid signaling in ASM have been definitively identified. Here, we show that the transcription factor, Krüppel-like factor 15 (KLF15), is directly induced by glucocorticoids in primary human ASM, and that KLF15 represses ASM hypertrophy. We integrated transcriptome data from KLF15 overexpression with genomewide analysis of RNA polymerase (RNAP) II and glucocorticoid receptor (GR) occupancy to identify phospholipase C delta 1 as both a KLF15-regulated gene and a novel repressor of ASM hypertrophy. Our chromatin immunoprecipitation sequencing data also allowed us to establish numerous direct transcriptional targets of GR in ASM. Genes with inducible GR occupancy and putative antiinflammatory properties included IRS2, APPL2, RAMP1, and MFGE8. Surprisingly, we also observed GR occupancy in the absence of supplemental ligand, including robust GR binding peaks within the IL11 and LIF loci. Detection of antibody-GR complexes at these areas was abrogated by dexamethasone treatment in association with reduced RNA polymerase II occupancy, suggesting that noncanonical pathways contribute to cytokine repression by glucocorticoids in ASM. Through defining GR interactions with chromatin on a genome-wide basis in ASM, our data also provide an important resource for future studies of GR in this therapeutically relevant cell type. © 2017 by the American Thoracic Society.


Helling B.A.,Aurora University | Yang I.V.,Aurora University | Yang I.V.,Center for Genes
Current Opinion in Pulmonary Medicine | Year: 2015

Purpose of review Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options and extensive gene expression changes identified in the lung parenchyma. Multiple lines of evidence suggest that epigenetic factors contribute to dysregulation of gene expression in IPF lung. Most importantly, risk factors that predispose to IPF - age, sex, cigarette smoke, and genetic variants - all influence epigenetic marks. This review summarizes recent findings of association of DNA methylation and histone modifications with the presence of disease and fibroproliferation. Recent findings In addition to targeted studies focused on specific gene loci, genome-wide profiles of DNA methylation demonstrate widespread DNA methylation changes in IPF lung tissue and a substantial effect of these methylation changes on gene expression. Genetic loci that have been recently associated with IPF also contain differentially methylated regions, suggesting that genetic and epigenetic factors act in concert to dysregulate gene expression in IPF lung. Summary Although we are in very early stages of understanding the role of epigenetics in IPF, the potential for the use of epigenetic marks as biomarkers and therapeutic targets is high and discoveries made in this field will likely bring us closer to better prognosticating and treating this fatal disease. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


News Article | December 16, 2015
Site: www.biosciencetechnology.com

Despite Congressional mandates aimed at diversifying clinical research, little has changed in the last 30 years in both the numbers of studies that include minorities and the diversity of scientists being funded, according to a new analysis by researchers at UC San Francisco. That lack of diversity could have a serious impact on our ability to care for the nearly 40 percent of the current U.S. population whose heritage includes non-European races, the authors said, and will increase in urgency as the proportion of minority residents exceeds 50 percent in 2044. The commentary, which was published Dec. 15 in the Policy Forum of online scientific journal PLoS Medicine, compiled 30 years of raw data on funding for research by non-White scientists, as well as two decades of analyses from the National Institutes of Health (NIH) and others regarding the percentage of clinical studies that include racial and ethnic minorities. They found that since the 1993 NIH Revitalization Act, which required all federally funded clinical research to prioritize the inclusion of women and minorities, less than 2 percent of the 10,000-plus cancer studies have included enough minorities to be relevant, and less than 5 percent of respiratory studies have. A separate Freedom of Information Act request also showed that the people best able to reach minority study participants – scientists from those communities – are consistently less likely to receive NIH funding, in terms of the percentage of their grants that are funded. Both the challenges and solutions are multifactorial, they said, but not insurmountable. “This country is plagued by racial and ethnic disparities in some of the deadliest and most debilitating diseases, including cancer, cardiovascular disease, diabetes and asthma,” said co-senior author Esteban González Burchard, M.D., MPH, a pulmonologist and professor of bioengineering and therapeutic sciences in the UCSF schools of Pharmacy and Medicine. “The only way we will make progress in decreasing that burden of disease is by understanding why it occurs. And we can’t understand that without including diverse communities in our research.” Those disparities also have economic consequences: The paper cited research showing that from 2003 to 2006, alone, racial and ethnic health disparities increased U.S. medical costs by more than $1.2 trillion. “Increasing diversity is also a worthwhile effort scientifically,” said first author Sam Oh, Ph.D., MPH, an epidemiologist and researcher in the UCSF Center for Genes, Environment and Health. “We can’t divert our resources knowing that an intervention is only going to work on a small portion of the population. By understanding that population, we can target our resources effectively for everyone. But we'll only learn that by having study populations that represent everyone.” The paper cites a number of medications that are known to affect people differently based on their genetic backgrounds, including the blood thinner clopidogrel, which is prescribed to reduce stroke risk after angioplasty, but is ineffective in the 50 percent of Asians who lack the enzyme to activate it. Other examples include the epilepsy drug carbamazepime, which is deadly to Asians who have the gene HLA-B*1502, and the asthma drug albuterol, which has a lower response rate among African-Americans. Burchard, who leads the nation’s largest gene-environment study on asthma in minority children in the United States, said there are multiple challenges to diversifying clinical studies, but those can be overcome through a commitment by funders and researchers alike. The paper noted that even though the 1993 mandate stipulated that cost could not be used to justify the failure to enroll diverse populations, which can cost more to reach effectively, no discussion of new mandates for research can take place without addressing “the crisis of declining inflation-adjusted NIH budgets.” This competitive funding environment, which the authors emphasized is beyond the control of the NIH, encourages researchers to reduce their grant proposals as much as possible in the hopes of being funded at all, which inadvertently encourages them to choose populations that are less expensive to reach. “The NIH alone will not be able to correct the disparities or inequities of the healthcare system,” the authors wrote, “but it can send a powerful message that may promote changes in our health care and health science systems.” The paper cited multiple known barriers for study participation by U.S. minorities, including limited access to specialty centers that refer patients to clinical studies, fear of exploitation in medical research, financial constraints, cultural and language barriers, and competing demands on time, among others. They offered a variety of approaches to address these, ranging from partnerships with community organizations to flexible study hours, targeted ads, payment, or food or travel support for participants. A significant impediment, they said, is the lack of diversity among the research and clinical professions. Not only are minority physicians and scientists more likely to conduct research in minority populations, but they also may be able to gain the trust of those communities more easily in recruitment. Yet these professionals remain underrepresented in medical and scientific communities. For example, African Americans and Hispanics represent 4.3 percent and 7.2 percent, respectively, of biomedical doctoral degrees in 2013, and less than 2 percent and 3.4 percent, respectively, of NIH-funded principal investigators. The U.S. Census bureau estimated that African-Americans made up 13.2 percent of the U.S. population in 2014, and Hispanics, 17.4 percent. Non-White scientists also are less likely to be awarded funding for their grants. In the new analysis, the authors found that the award rate for the gold-standard R01 or equivalent grants has remained consistently lower among minority applicants than Whites for three decades. In 1985, 42.1 percent of non-White researchers’ grant applications were funded, versus 48.6 percent for Whites. By 2013, both had declined to 19.3 percent versus 23.3 percent – a smaller spread, but greater percentage difference. The authors applauded the NIH’s current efforts to address these issues, including actively soliciting feedback to diversify President Obama’s Precision Medicine Initiative, for which Burchard is a member of the NIH-appointed working group. They also recommended other possible approaches, including increasing NIH funding overall; diversifying the committees that review grant applications, which remain 90 percent White; formally including minority recruitment among the criteria for determining scientific merit of studies; and empowering the NIH to set and enforce similar requirements for minority recruitment as it does for gender. “Diversity in science is science done well,” said Oh. “You need diversity in the research, diversity in who is being studied and diversity in the people doing the science. Otherwise you become an echo chamber – everyone looks and sounds just like us.”


Yang I.V.,Center for Genes | Yang I.V.,University of Colorado at Denver
Epigenomics | Year: 2012

Idiopathic pulmonary fibrosis (IPF) is a complex lung disease of unknown etiology. Development of IPF is influenced by both genetic and environmental factors. Gene-expression profiling studies have taught us quite a bit about the biology of this fatal disease, but epigenetic marks may be the missing link that connects the environmental exposure in genetically predisposed individuals to transcriptome changes associated with the development of IPF. This review will begin with an introduction to the disease, followed by brief summaries of studies of gene expression in IPF and epigenetic marks associated with exposures relevant to IPF. The majority of the discussion will focus on epigenetic studies conducted so far in IPF, the limitations, challenges nd future directions in this field. © 2012 Future Medicine Ltd.


Seibold M.A.,Center for Genes | Schwartz D.A.,Center for Genes | Schwartz D.A.,University of Colorado at Denver
Annual Review of Physiology | Year: 2011

Common lung diseases such as asthma, COPD, and pulmonary fibrosis cause significant morbidity and mortality in the U.S. and worldwide. Research investigating the mechanisms of disease etiology has clearly indicated that genetic attributes and environmental exposures each play important roles in the development of these diseases. Emerging evidence underscores the importance of the interplay between genetic predisposition and environmental factors in fully understanding the development of lung disease. Herein we discuss recent advances in knowledge and technology surrounding the role of genetics, the environment, and gene-environment interactions in these common lung diseases. © 2011 by Annual Reviews. All rights reserved.


Garantziotis S.,National Health Research Institute | Schwartz D.A.,Center for Genes
Annual Review of Public Health | Year: 2010

Gene-environment interactions are the indisputable cause of most respiratory diseases. However, we still have very limited understanding of the mechanisms that guide these interactions. Although the conceptual approaches to environmental genomics were established several decades ago, the tools are only now available to better define the mechanisms that underlie the interactions among these important etiological features of lung disease. In this article, we summarize recent insights in the environmental genomics (ecogenomics) of common nonmalignant respiratory diseases (asthma, COPD, pulmonary fibrosis, and respiratory infections), describe the framework of gene-environment interactions that inform the pathogenesis of respiratory diseases, and propose future research directions that will help translate scientific advances into public health gains. Copyright © 2010 by Annual Reviews. All rights reserved.


DiStefano J.K.,Center for Genes | Gerhard G.S.,Temple University
Expert Review of Gastroenterology and Hepatology | Year: 2016

Liver biopsy is currently recognized as the most accurate method for diagnosing and staging nonalcoholic fatty liver disease (NAFLD). However, this procedure is typically performed when disease has progressed to clinically significant stages, thereby limiting early diagnosis of patients who are at high risk for development of liver- and cardiovascular-related morbidity and mortality. Recently, microRNAs (miRNAs), short, noncoding RNAs that regulate gene expression, have been associated with histological features of NAFLD and are readily detected in the circulation. As such, miRNAs are emerging as potentially useful noninvasive markers with which to follow the progression of NAFLD. In this article, we present the evidence linking circulating miRNAs with NAFLD and discuss the potential value of circulating miRNA profiles in the development of improved methods for NAFLD diagnosis and clinical monitoring of disease progression. © 2015 Taylor & Francis.


Steele M.P.,Vanderbilt University | Schwartz D.A.,Aurora University | Schwartz D.A.,Center for Genes
Annual Review of Medicine | Year: 2013

There is clear evidence that environmental exposures and genetic predisposition contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cigarette smoking increases the risk of developing IPF several-fold, as do other exposures such as metal-fume and wood-dust exposure. Occupations that increase the risk of IPF are agricultural work, hairdressing, and stone polishing, supporting the role of environmental exposure in disease pathogenesis. Genetic predisposition to IPF is evident from its familial aggregation and the fact that pulmonary fibrosis develops in several rare genetic disorders. Mutations in surfactant proteins lead to pulmonary fibrosis and are associated with endoplasmic reticulum stress in alveolar type II epithelial cells. Mutations in telomerase have been found in several families with IPF, and shortened telomeres are found in sporadic cases of IPF. A common variant in mucin 5B predisposes to both familial and sporadic IPF and is present in the majority of cases, indicating sporadic IPF occurs in those with genetic predisposition. Copyright © 2013 by Annual Reviews.


Yang I.V.,Center for Genes | Yang I.V.,Aurora University | Schwartz D.A.,Center for Genes | Schwartz D.A.,Aurora University
American Journal of Respiratory and Critical Care Medicine | Year: 2011

Epigenetics is traditionally defined as the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence. There are three main classes of epigenetic marks - DNA methylation, modifications of histone tails, and noncoding RNAs - each of which may be influenced by the environment, diet, diseases, and ageing. Importantly, epigenetic marks have been shown to influence immune cell maturation and are associated with the risk of developing various forms of cancer, including lung cancer. Moreover, there is emerging evidence that these epigenetic marks affect gene expression in the lung and are associated with benign lung diseases, such as asthma, chronic obstructive pulmonary disease, and interstitial lung disease. Technological advances have made it feasible to study epigenetic marks in the lung, and it is anticipated that this knowledge will enhance our understanding of the dynamic biology in the lung and lead to the development of novel diagnostic and therapeutic approaches for our patients with lung disease.


Schwartz D.A.,Center for Genes
Proceedings of the American Thoracic Society | Year: 2010

Gene-environment interactions are the indisputable cause of most respiratory diseases. However,we still have very limited understanding of the mechanisms that guide these interactions. Although the conceptual approaches to environmental genomics were established several decades ago, the tools are only nowavailable to better define the mechanisms that underlie the interaction between these important etiologic features of lung disease. Epigenetic mechanisms can mediate the effect of the environment on thehuman genomeby controlling the transcriptional activity of specific genes, at specific points in time, in specific organs. In this article, we demonstrate the potential importance of epigenetic mechanisms in the development and progression of chronic obstructive pulmonary disease and asthma.

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