Frederick L. Tyson

Community-based participatory research: opportunities, challenges, and the need for a common language.

In January of 2002, a call for papers featuring community-based participatory research (CBPR) was issued. The intent was to highlight the outstanding work being done in this area and the role CBPR can play in improving the care and outcomes of populations at-risk.1 What emerged from this call was more than what any of the editors expected, and has been illustrative of both the superb scholarship and community engagement occurring in CBPR and how much more can be done in refining and broadening the application of CBPR in what we do. The body of research submitted for consideration also highlights several important realities: 1) CBPR is appropriate and applicable across disciplines and within many diverse community settings; 2) the potential for CBPR to make meaningful contributions to improving the health and well-being of traditionally disenfranchised population groups and communities is very real and, in many instances, being realized; and 3) we need to do a better job of articulating CBPR to our peers and colleagues as “research-plus” that is both methodologically rigorous and that makes unique contributions not possible using other means. The 11 original research papers presented in this Special Issue came from an impressive pool of 81 submissions. And while CBPR may seem somewhat straightforward in theory, as these articles demonstrate, the degree to which CBPR is applied and how it is represented are far more diverse and varied. The peer review process and several editor meetings for this Special Issue brought out many of the challenges inherent in CBPR. How do we define community? What is a meaningful impact? How do we distinguish between community-placed and community-based research? How do we balance the importance of the research process with the importance of the research product or findings? Is there a methodologic threshold with which to determine whether a project is or is not CBPR? What is evident from the submissions is how broadly CBPR is being applied, geographically, within specific population groups and clinical scenarios, and methodologically. For example, Angell et al.2 and Stratford et al.3 both describe CBPR projects in rural settings, while van Olphen et al.,4 Horowitz et al.,5 and Masi et al.6 all describe urban-based research. Initiatives targeting specific vulnerable or at-risk populations are featured in work by Lauderdale et al.7 with older Chinese immigrants, by Lam et al.8 with Vietnamese-American women, and by van Olphen et al. with African-American women. Similarly, CBPR was clearly applicable in several different clinical scenarios, including chronic disease management of diabetes,5 asthma,9 and cancer treatment and prevention.10 The partners engaged in the community-based research also varied across projects and included faith-based organizations,4,10 neighborhood and community leaders,6,8 and social service and support agencies.2,3,7 Finally, the research topics and interventions themselves also reflected a wide spectrum of CBPR applications. Sloane et al. examined the degree of nutritional resources available within a community, whereas Masi et al. evaluated the application of internet-based technologies.5,11 The articles presented also reflect the broad scope of research in which CBPR can be applied methodologically. Angell et al. and Corbie-Smith et al. report on findings where CBPR was applied to randomized controlled trials,2,10 while van Olphen et al., Masi et al., and Lam et al., all report data from intervention studies with pre–post comparisons.4,6,8 Horowitz et al. and Lauderdale et al. represent good examples of CBPR applied to survey research,5,7 and Parker et al. demonstrate CBPR applied to a qualitative study.9 Finally, the article by Nyden provides an overview of CBPR and highlights many of the issues and struggles to institutionalizing and legitimizing CBPR within the broader research community from an academic perspective.12 As the science and field of CBPR advance to the next level, it is clear that several things need to occur. We need more formal training in CBPR that is more broadly available to both academically-based researchers and community members. Post-doctoral training programs such as the Kellogg Community Scholars Program13 need to be expanded beyond the current 3 schools of public health, and need to be integrated into other health professional schools and within other established fellowship and post-doctoral training programs. Additionally, career development awards sponsored by federal agencies and private philanthropies need to be amenable to proposals that engage the candidate in CBPR projects and ideally should promote this in their solicitation and review process. We also need to encourage scholarship, not only in the application of CBPR, but also in better understanding the nuances of the model, so that it can truly live up to its potential. This includes developing a common language for describing CBPR-related research in the health services literature, so that it can stand on its own merits and be appreciated for the contributions it brings to the field. One possible framework for this common language is introduced in Table 1 and is meant to serve as a resource for authors considering submission of CBPR projects to peer-reviewed journals. Finally, we need to gain a greater appreciation for CBPR as “research-plus” that is reflected in funding priorities, review criteria, community empowerment, and academic advancement. Table 1 Proposed Process for Describing Community-based Participatory Research Findings in Health Sciences Literature In summary, it is best to view this Special Issue as a reflection of both where we are as a research community and where we need to go. The 11 papers ultimately chosen for this issue represent a small fraction of the excellent work ongoing in many of our communities. Yet there is much more than can and should be done. As the gap in health access and health outcomes grows wider and is further defined by socioeconomics, race, language, country of origin, and other markers and designations inherent in a multicultural, multiethnic society, we need CBPR to help find the answers and sustainable solutions.

Mitochondria, energetics, epigenetics, and cellular responses to stress

Background: Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways not only through energetics and ATP production but also through metabolites generated in the tricarboxylic acid cycle, as well as mitochondria–nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation. Objectives: We investigated the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and we examined DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function. Methods: The National Institute of Environmental Health Sciences sponsored the Workshop on Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response on 25–26 March 2013. Here, we summarize key points and ideas emerging from this meeting. Discussion: A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways. Conclusions: Understanding mitochondria–cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors. Citation: Shaughnessy DT, McAllister K, Worth L, Haugen AC, Meyer JN, Domann FE, Van Houten B, Mostoslavsky R, Bultman SJ, Baccarelli AA, Begley TJ, Sobol RW, Hirschey MD, Ideker T, Santos JH, Copeland WC, Tice RR, Balshaw DM, Tyson FL. 2014. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect 122:1271–1278; http://dx.doi.org/10.1289/ehp.1408418

Environmental Epigenomics, Imprinting and Disease Susceptibility

On Tuesday, November 2, 2005 over 450 scientists representing 14 nations converged on the Washington Duke Inn, Durham, NC, USA to discuss, learn and exchange information on how environmental influences can exert impacts on health not only on the individual that has been exposed but also for up to four subsequent generations in some human and animal models tested. The meeting entitled “Environmental Epigenomics, Imprinting and Disease Susceptibility” was sponsored by the National Institute of Environmental Health Sciences (NIEHS) and the Duke Comprehensive Cancer Center. The meeting featured presentations from many of the leading authorities/experts in epigenomics in the world and approximately 70 poster presentations, of which twelve were selected for oral presentation. The meeting was organized into nine scientific sessions spread over two and a half days that addressed the fetal basis of disease, epigenetics and gene regulation, epigenetics and cancer, therapeutic and reproductive cloning, stem cell differentiation, epigenetics and chronic diseases and epigenetics and neurodevelopment. The opening session introduced the meeting co-organizers, Randy Jirtle of Duke University Medical Center and Frederick Tyson of NIEHS, to conference participants and included greetings from. Christopher Willett, Chair of Duke Radiation Oncology Department, and William Schlessinger, Dean of the Nicolas School of the Environment and Earth Sciences. David Schwartz, Director of the NIEHS, set the tone for the conference with an overview lecture that identified research priorities of the NIEHS and pointed out the intersections between the environmental genomics component of NIEHS priorities and the environmental epigenomics. He noted that NIEHS research priorities will emphasize and coordinate efforts aimed at the study of complex human diseases. The environmental genomics infrastructural resources developed by NIEHS including over 500 re-sequenced environmentally responsive genes, over 50 humanized mouse strains, and progress towards establishing gene expression standards are available for utilization in the integration of epigenomic studies and the analysis of complex human diseases. Just as epigenomics is becoming increasingly more important in Schwartz’s own asthma research, this conference identified additional opportunities for the integration of environmental epigenomics and complex human disease.

Chromosomal changes in high- and low-invasive mouse lung adenocarcinoma cell strains derived from early passage mouse lung adenocarcinoma cell strains

The incidence of adenocarcinoma of the lung is increasing in the United States, however, the difficulties in obtaining lung cancer families and representative samples of early to late stages of the disease have lead to the study of mouse models for lung cancer. We used Spectral Karyotyping (SKY), mapping with fluorescently labeled genomic clones (FISH), comparative genomic hybridization (CGH) arrays, gene expression arrays, Western immunoblot and real time polymerase chain reaction (PCR) to analyze nine pairs of high-invasive and low-invasive tumor cell strains derived from early passage mouse lung adenocarcinoma cells to detect molecular changes associated with tumor invasion. The duplication of chromosomes 1 and 15 and deletion of chromosome 8 were significantly associated with a high-invasive phenotype. The duplication of chromosome 1 at band C4 and E1/2-H1 were the most significant chromosomal changes in the high-invasive cell strains. Mapping with FISH and CGH array further narrowed the minimum region of duplication of chromosome 1 to 71-82 centimorgans (cM). Expression array analysis and confirmation by real time PCR demonstrated increased expression of COX-2, Translin (TB-RBP), DYRK3, NUCKS and Tubulin-alpha4 genes in the high-invasive cell strains. Elevated expression and copy number of these genes, which are involved in inflammation, cell movement, proliferation, inhibition of apoptosis and telomere elongation, were associated with an invasive phenotype. Similar linkage groups are altered in invasive human lung adenocarcinoma, implying that the mouse is a valid genetic model for the study of the progression of human lung adenocarcinoma.

New insights and updated guidelines for epigenome-wide association studies☆

Abstract Epigenetic dysregulation in disease is increasingly studied as a potential mediator of pathophysiology. The epigenetic events are believed to occur in somatic cells, but the limited changes of DNA methylation in studies to date indicate that only subsets of the cells tested undergo epigenetic dysregulation. The recognition of this subpopulation effect indicates the need for care in design and execution of epigenome-wide association studies (EWASs), paying particular attention to confounding sources of variability. To maximize the sensitivity of the EWASs, ideally, the cell type mediating the disease should be tested, which is not always practical or ethical in human subjects. The value of using accessible cells as surrogates for the target, disease-mediating cell type has not been rigorously tested to date. In this review, participants in a workshop convened by the National Institutes of Health update EWAS design and execution guidelines to reflect new insights in the field.

Community Resources and Technologies Developed Through the NIH Roadmap Epigenomics Program

This chapter describes resources and technologies generated by the NIH Roadmap Epigenomics Program that may be useful to epigenomics researchers investigating a variety of diseases including cancer. Highlights include reference epigenome maps for a wide variety of human cells and tissues, the development of new technologies for epigenetic assays and imaging, the identification of novel epigenetic modifications, and an improved understanding of the role of epigenetic processes in a diversity of human diseases. We also discuss future needs in this area including exploration of epigenomic variation between individuals, single-cell epigenomics, environmental epigenomics, exploration of the use of surrogate tissues, and improved technologies for epigenome manipulation.

The NIEHS TaRGET II Consortium and environmental epigenomics

225 in response to pertinent environmental exposures. Additionally, it is impossible to sample all relevant tissues involved in disease pathogenesis in human populations. To make direct connections between exposure-induced epigenetic changes and health outcomes, it is therefore critical to determine whether epigenetic alterations are conserved across tissues in such a way that easily sampled surrogate tissues could be used to assess the impact of environmental exposure on diseaserelevant but inaccessible target tissues (Table 1). The correlation between The NIEHS TaRGET II Consortium and environmental epigenomics

Base-Resolution Analysis of DNA Methylation Patterns Downstream of Dnmt3a in Mouse Naïve B Cells

The DNA methyltransferase, Dnmt3a, is dynamically regulated throughout mammalian B cell development and upon activation by antigenic stimulation. Dnmt3a inactivation in hematopoietic stem cells has been shown to drive B cell-related malignancies, including chronic lymphocytic leukemia, and associates with specific DNA methylation patterns in transformed cells. However, while it is clear that inactivation of Dnmt3a in hematopoietic stem cells has profound functional effects, the consequences of Dnmt3a inactivation in cells of the B lineage are unclear. To assess whether loss of Dnmt3a at the earliest stages of B cell development lead to DNA methylation defects that might impair function, we selectively inactivated Dnmt3a early in mouse B cell development and then utilized whole genome bisulfite sequencing to generate base-resolution profiles of Dnmt3a+/+ and Dnmt3a−/− naïve splenic B cells. Overall, we find that global methylation patterns are largely consistent between Dnmt3a+/+ and Dnmt3a−/− naïve B cells, indicating a minimal functional effect of DNMT3A in mature B cells. However, loss of Dnmt3a induced 449 focal DNA methylation changes, dominated by loss-of-methylation events. Regions found to be hypomethylated in Dnmt3a−/− naïve splenic B cells were enriched in gene bodies of transcripts expressed in B cells, a fraction of which are implicated in B cell-related disease. Overall, the results from this study suggest that factors other than Dnmt3a are the major drivers for methylome maintenance in B cell development.

Dosage compensation and DNA methylation landscape of the X chromosome in mouse liver

DNA methylation plays a key role in X-chromosome inactivation (XCI), a process that achieves dosage compensation for X-encoded gene products between mammalian female and male cells. However, differential sex chromosome dosage complicates genome-wide epigenomic assessments, and the X chromosome is frequently excluded from female-to-male comparative analyses. Using the X chromosome in the sexually dimorphic mouse liver as a model, we provide a general framework for comparing base-resolution DNA methylation patterns across samples that have different chromosome numbers and ask at a systematic level if predictions by historical analyses of X-linked DNA methylation hold true at a base-resolution chromosome-wide level. We demonstrate that sex-specific methylation patterns on the X chromosome largely reflect the effects of XCI. While our observations concur with longstanding observations of XCI at promoter-proximal CpG islands, we provide evidence that sex-specific DNA methylation differences are not limited to CpG island boundaries. Moreover, these data support a model in which maintenance of CpG islands in the inactive state does not require complete regional methylation. Further, we validate an intragenic non-CpG methylation signature in genes escaping XCI in mouse liver. Our analyses provide insight into underlying methylation patterns that should be considered when assessing sex differences in genome-wide methylation analyses.