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Douglas A. Bell, Ph.D.

Senior Investigator
Molecular Genetics Laboratory/Environmental Genomics Group
NIEHS
Building 101, Room A308
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
919-541-7686

Research Topics

The Environmental Genomics Group works to characterize underlying factors that contribute to variability in human toxicological responses. We especially focus on discovery of human alleles or epigenetic factors that modify responses to exposure and we investigate how such factors affect risk in exposed people. This basic information will be useful in determining appropriate variability parameters in human risk estimation models, in identifying at-risk individuals and in devising disease-prevention strategies.

The NIEHS Environmental Genome Project and the 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 Genomics Group is developing novel methods to identify SNPs that regulate gene expression or that measure their functional impact in vitro and in vivo. Thus, the group's overall objective is to identify sequence variants 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 gene regulation information from parent cell to daughter cells and from one generation to the next that is encoded in methyl-CpGs, histone modifications or noncoding RNAs. Epigenetic factors such as chromatin state may modulate the impact of exposure, or conversely, exposure can directly alter epigenetic status such as DNA methylation level in regulatory sequences (Joubert et al 2012). Determining the functional impact of exposure-induced changes in methylation is an active area of interest for our group.

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)
  • Evaluation of the role of these factors in exposed individuals and in environmentally-induced disease

Current Projects:

  • Computational discovery and functional analysis of p53, AhR, and NRF2 transactivation target sequences (response elements) to assess the impact of SNPs on regulation of responsive genes (Noureddine et al., 2009, Wang et al 2011).
  • Identifying exposure-induced methylation patterns in blood cell DNA (Joubert et al 2012). In a project led by Dr. Stephanie London (Epidemiology Branch) we have identified that maternal smoking produces highly significant (p<10-15) changes in the methylation status of genes in fetal cord blood. Genes involved in carcinogen metabolism and hematopoietic stem cell renewal were strongly affected. Adult smokers display similar exposure-induced methylation patterns in their blood and we are determining the usefulness of these patterns as biomarkers of tobacco exposure. Using cell separation techniques we are currently examining the impact of exposure on isolated hematopoietic cells from adults and neonates.
  • Understanding the role of chromatin state, dynamics, and methylation status on exposure-induced transcription of genes in the p53, AhR and NRF2 pathways.

Biography

Dr. Bell received a B.S. degree from Cornell University in 1975, and a Ph.D. in Environmental Biology from the University of North Carolina at Chapel Hill in 1988. Following postdoctoral fellowships at UNC-CH and U.S. Environmental Protection Agency he joined the National Institute of Environmental Health Sciences in 1990 becoming a Senior Investigator in 1996. He currently heads the Environmental Genomics Group in the Laboratory of Molecular Genetics, NIEHS.

Selected Publications

  1. Noureddine MA, Menendez D, Campbell MR, Bandele OJ, Horvath MM, Wang X, Pittman GS, Chorley BN, Resnick MA, Bell DA. Probing the functional impact of sequence variation on p53-DNA interactions using a novel microsphere assay for protein-DNA binding with human cell extracts. PLoS Genet. 2009;5(5):e1000462.
  2. Wang X, Chorley BN, Pittman GS, Kleeberger SR, Brothers J 2nd, Liu G, Spira A, Bell DA. Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer. PLoS One. 2010;5(8):e11934.
  3. Chorley BN, Campbell MR, Wang X, Karaca M, Sambandan D, Bangura F, Xue P, Pi J, Kleeberger SR, Bell DA. Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res. 2012;40(15):7416-29.
  4. Joubert BR, Håberg SE, Nilsen RM, Wang X, Vollset SE, Murphy SK, Huang Z, Hoyo C, Midttun Ø, Cupul-Uicab LA, Ueland PM, Wu MC, Nystad W, Bell DA, Peddada SD, London SJ. 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Environ Health Perspect. 2012;120(10):1425-31.
This page was last updated on April 2nd, 2013