Yang et al discuss the study by Oldham and colleagues which report the results of a two-stage, multicenter, international genome-wide association studies (GWAS) of transplant-free survival. Using a ...staged analysis approach, the authors identified four genetic variants associated with transplant-free survival, with consistent effect direction in the two stages of genetic association analyses. They comment that this is an important study that identified a novel risk variant that appears to affect survival and a protein that may become another important therapeutic target in this devastating and largely untreatable disease. However, there are also a number of unanswered questions that will require further investigation.
Despite advances in therapeutics and a better understanding of environmental contributions, ethnic disparities are profound in asthma; asthma prevalence is >2 times higher in African compared to ...European Americans, and African American children are >3 times more likely to be hospitalized and die from asthma than whites. Epigenetic marks, including DNA methylation, are a key mechanistic component of gene‐environment interactions that affect gene expression, respiratory epithelial dysfunction, and immune cell skewing in asthma. Our group performed pioneering work to identify asthma associated‐DNA methylation changes that affect gene expression in African American inner city children. Our work identified 81 differentially methylated regions (DMRs) in peripheral blood mononuclear cells (PBMCs) associated with allergic asthma. DNA methylation changes in PBMCs are small (median 1.3%; range 0.02%‐3.1%) but consistent with the majority of DMRs hypomethylated in asthma, including important immune genes such as IL‐13, RUNX3, and TIGIT. In the nasal epithelia, we identified much larger (median 9.5%, range: 2.6‐29.5%) methylation changes, both in the form of single CpG methylation (differentially methylated positionsDMPs) and regions (DMRs). 60% of genes that are differentially expressed in the asthmatic nasal epithelium have significant associations of DNA methylation and gene expression; these include asthma genes (ALOX15, CAPN14, POSTN), genes involved in inflammation and immunity, cell adhesion, extracellular matrix, obesity and autophagy, and epigenetic regulators, among others. Importantly, these results have been replicated in multiple cohorts, including a cohort of Puerto Rican children, another population that shares an unproportional disease burden. We are currently involved in projects that aim to integrate genetic ancestry, DNA methylation, and gene expression data to better understand genetic underpinnings of these DNA methylation changes. Our earlier work also showed that nasal epithelia capture disease activity seen in the lung airway epithelia but that there are many more significant associated DNA methylation changes in the nasal epithelia, suggesting an important role for the environment in influencing these epigenetic changes and the need to understand environmental exposures that are driving these changes. In summary, our findings that epigenetic marks in respiratory epithelia are associated with allergic asthma in inner‐city children provide new targets for understanding the biology of the disease, developing biomarkers of exposure or disease, and potentially identifying novel therapeutic approaches for this disease.
Asthma is a common complex respiratory disease characterized by chronic airway inflammation and partially reversible airflow obstruction resulting from genetic and environmental determinants. Because ...epigenetic marks influence gene expression and can be modified by both environmental exposures and genetic variation, they are increasingly recognized as relevant to the pathogenesis of asthma and may be a key link between environmental exposures and asthma susceptibility. Unlike changes to DNA sequence, epigenetic signatures are dynamic and reversible, creating an opportunity for not only therapeutic targets but may serve as biomarkers to follow disease course and identify molecular subtypes in heterogeneous diseases such as asthma. In this review, we will examine the relationship between asthma and 3 key epigenetic processes that modify gene expression: DNA methylation, modification of histone tails, and noncoding RNAs. In addition to presenting a comprehensive assessment of the existing epigenetic studies focusing on immune regulation in asthma, we will discuss future directions for epigenetic investigation in allergic airway disease.
comb-p is a command-line tool and a python library that manipulates BED files of possibly irregularly spaced P-values and (1) calculates auto-correlation, (2) combines adjacent P-values, (3) performs ...false discovery adjustment, (4) finds regions of enrichment (i.e. series of adjacent low P-values) and (5) assigns significance to those regions. In addition, tools are provided for visualization and assessment. We provide validation and example uses on bisulfite-seq with P-values from Fisher's exact test, tiled methylation probes using a linear model and Dam-ID for chromatin binding using moderated t-statistics. Because the library accepts input in a simple, standardized format and is unaffected by the origin of the P-values, it can be used for a wide variety of applications.
comb-p is maintained under the BSD license. The documentation and implementation are available at https://github.com/brentp/combined-pvalues.
bpederse@gmail.com
Epigenetics of idiopathic pulmonary fibrosis Yang, Ivana V; Schwartz, David A
Translational research : the journal of laboratory and clinical medicine,
01/2015, Letnik:
165, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Idiopathic pulmonary fibrosis (IPF) is a complex lung disease of unknown etiology. Development of IPF is influenced by both genetic and environmental factors. Recent work by our and other groups has ...identified strong genetic predisposition factors for the development of pulmonary fibrosis, and cigarette smoke remains the most strongly associated environmental exposure risk factor. Gene expression profiling studies of IPF lung have taught us quite a bit about the biology of this fatal disease, and those of peripheral blood have provided important biomarkers. However, epigenetic marks may be the missing link that connects the environmental exposure in genetically predisposed individuals to transcriptional changes associated with disease development. Moreover, epigenetic marks represent a promising therapeutic target for IPF. In this review, the disease is introduced, genetic and gene expression studies in IPF are summarized, exposures relevant to IPF and known epigenetic changes associated with cigarette smoke exposure are discussed, and epigenetic studies conducted so far in IPF are summarized. Limitations, challenges, and future opportunities in this field are also discussed.
The environment, epigenome, and asthma Yang, Ivana V; Lozupone, Catherine A; Schwartz, David A
Journal of allergy and clinical immunology
140, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Asthma prevalence has been on the increase, especially in North America compared with other continents. However, the prevalence of asthma differs worldwide, and in many countries the prevalence is ...stable or decreasing. This highlights the influence of environmental exposures, such as allergens, air pollution, and the environmental microbiome, on disease etiology and pathogenesis. The epigenome might provide the unifying mechanism that translates the influence of environmental exposures to changes in gene expression, respiratory epithelial function, and immune cell skewing that are hallmarks of asthma. In this review we will introduce the concept of the environmental epigenome in asthmatic patients, summarize previous publications of relevance to this field, and discuss future directions.
The airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, ...idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.
Characterization of the epigenome is a primary interest for children's environmental health researchers studying the environmental influences on human populations, particularly those studying the ...role of pregnancy and early-life exposures on later-in-life health outcomes.
Our objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children's Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis.
We address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research.
A common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children's health.
The dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Myocardial ischemia-reperfusion injury (IRI) leads to the stabilization of the transcription factors hypoxia-inducible factor 1-alpha (HIF1-alpha) and hypoxia-inducible factor 2-alpha (HIF2-alpha). ...While previous studies implicate HIF1-alpha in cardioprotection, the role of HIF2-alpha remains elusive. Here we show that HIF2-alpha induces the epithelial growth factor amphiregulin (AREG) to elicit cardioprotection in myocardial IRI. Comparing mice with inducible deletion of Hif1a or Hif2a in cardiac myocytes, we show that loss of Hif2-alpha increases infarct sizes. Microarray studies in genetic models or cultured human cardiac myocytes implicate HIF2-alpha in the myocardial induction of AREG. Likewise, AREG increases in myocardial tissues from patients with ischemic heart disease. Areg deficiency increases myocardial IRI, as does pharmacologic inhibition of Areg signaling. In contrast, treatment with recombinant Areg provides cardioprotection and reconstitutes mice with Hif2a deletion. These studies indicate that HIF2-alpha induces myocardial AREG expression in cardiac myocytes, which increases myocardial ischemia tolerance.
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