- Douglas A. Bell, Ph.D.
- Tel 984-287-3862
- P.O. Box 12233Mail Drop C3-03Durham, N.C. 27709
Douglas A. Bell, Ph.D., heads the Environmental Epigenomics and Disease Group and holds secondary appointments in the NIEHS Epigenetics and Stem Cell Laboratory and the NIEHS Genome Integrity and Structural Biology Laboratory.
The Environmental Epigenomics and Disease Group works to characterize underlying factors that contribute to variability in human toxicological responses. We especially focus on discovery of human alleles and epigenetic factors that modify responses to exposure and we investigate how such factors affect risk in exposed people. This basic information will be useful for understanding variability in human risk estimation models, and potentially, for identifying at-risk individuals and devising disease-prevention strategies.
Having uncovered the genetic basis for several susceptibility phenotypes in carcinogen metabolism, the group has developed high-throughput genotyping assays and worked with epidemiologists to further explore the gene-environment interaction component of exposure-induced disease. Several genotypes affecting carcinogen metabolism and DNA repair have been identified as susceptibility factors in environmentally-induced disease. The group’s gene-environment interaction studies on polymorphisms in GSTM1 (Bell et al., 1993) and N-acetyltransferase (Taylor et al., 1998) in bladder cancer have been highly cited.
The NIEHS Environmental Genome Project and the NIH 1000 Genomes Project have uncovered millions of sequence variants in the human genome. However, relatively few of these single nucleotide polymorphisms (SNPs) affect protein structure. Perhaps more SNPs will affect gene expression related to environmental stress responses, but methods for studying this are not established. The Environmental Epigenomics and Disease Group has developed novel methods that identify SNPs and methylation changes in environmentally responsive enhancers (Figure 1) and have evaluated functional impact on transcription factor binding (Figure 1a, b), gene expression and cellular phenotype. Thus, the group’s overall objective is to identify factors that modulate exposure responses and to evaluate their roles in human susceptibility to environmentally-induced disease using a variety of functional approaches.
Epigenetics is the nongenetic transmission of information encoded in methyl-CpGs, histone modifications or microRNAs, from parent cell to daughter cells and from one generation to the next. Epigenetic factors such as chromatin state may modulate the impact of exposure, or conversely, exposures such as tobacco smoke can directly alter epigenetic status including DNA methylation levels in enhancer regulatory sequences (Joubert et al, 2012) (Figure 2a) (Reynolds et al, 2015). Determining the functional impact of exposure-induced changes in methylation, such as the effect on transcription, is an active area of interest for our group (Figure 2b).
Major areas of research:
- Identification of epigenetic factors and sequence variants that modulate exposure responses regulated by the Ah receptor (carcinogen metabolism), NRF2 (oxidative stress), and p53 (DNA damage) (Figure 1).
- Evaluation of the role of these factors in environmentally-induced disease.
- Computational discovery and functional analysis of p53 and NRF2 transactivation target sequences (response elements) (Tomso et al., 2005; Wang et al., 2007; Bandele et al 2011; Chorley et al., 2012) (Figure 1a). The group is developing and applying novel bioinformatics methods including phylogenetic analysis (Horvath et al., 2007; Wang et al., 2007) and new functional assays to assess the impact of SNPs on regulatory elements in p53; (Noureddine et al., 2009; Bandele et al., 2011; Zeron-Median et al., 2013; Wang et al., 2015) and NRF2-responsive genes (Wang et al 2011). These studies will help us understand the role of chromatin state, dynamics, and methylation status on exposure-induced transcription of genes in the p53, AhR and NRF2 pathways (Figure 1b)
- Identifying exposure-induced methylation patterns in blood cell DNA. In a project led by Dr. Stephanie London (Epidemiology Branch) we have identified that maternal smoking produces highly significant changes in the methylation status of genes in fetal cord blood. Genes involved in carcinogen metabolism and hematopoietic progenitor cell proliferation were strongly affected (Joubert et al., 2012). The Environmental Epigenomics and Disease Group has extended this work to determine that several of these genes, such as AHRR, are also strongly affected in the blood of adult smokers (Figure 2a). We are currently examining the impact of tobacco smoke exposure on DNA methylation in purified leukocyte cell types from adult smokers and in a mouse model using whole genome sequencing techniques.
- In an FDA Center for Tobacco Research funded project, the group is validating DNA methylation change as a biomarker of tobacco smoke exposure. We are also identifying which cell type or tissue may be the most useful for monitoring tobacco associated changes in DNA methylation.
Bell received his Ph.D. and M.S. in environmental chemistry and biology from the University of North Carolina at Chapel Hill and a B.S. from Cornell University. He is adjunct Professor in the Department of Epidemiology, University of North Carolina at Chapel Hill. He has published over 130 peer-reviewed articles in leading biomedical journals, as well as several book chapters.
He served as Senior Editor for Biomarkers at Cancer Epidemiology Biomarkers and Prevention and has held a number of editorial board positions, including, Pharmacogenetics and Environmental Health Perspectives and has given over 80 invited lectures in the United States, Europe, Asia and South America. He served as elected chair of the Molecular Epidemiology Group, American Association of Cancer Research and president of the NIEHS faculty (Assembly of Scientists).