David J. Waxman

Our research program encompasses the following three major questions:

1. How do hormone regulatory circuits and epigenomic mechanisms intersect to regulate complex patterns of gene expression in mammalian tissues?
2. By which mechanisms does prenatal exposure to environmental chemicals with hormone-like properties reprogram developing tissues, leading to impaired reproductive function and an increase in adult onset disease?
3. Can improved strategies for cancer treatment be devised through a better understanding of the impact of cancer chemotherapy on host-tumor interactions affecting tumor angiogenesis and immune responses to cancer therapy?

Mechanisms regulating sex differences in liver gene expression – This project aims to elucidate global (genome-wide) transcriptional and epigenetic networks that dictate the sex-differential expression of more than 1,000 genes in mammalian liver; these sex-differential gene profiles have been linked to clinically relevant sex differences in hepatic drug metabolism, lipid metabolic profiles, and cardiovascular disease risk. Current research efforts combine powerful next generation sequencing technologies with bioinformatics to elucidate global regulatory mechanisms. These technologies include transcriptional profiling (single-strand RNA-seq), transcription factor location analysis (ChIP-seq), chromatin accessibility analysis, to identify open chromatin (regulatory) regions in the genome (DNase-seq), and RNA interaction analysis (RIP-seq). The rich, genome wide data sets that result are being analyzed to identify: (a) the unique chromatin states that characterize genes showing sex differences in their expression, and the epigenetic mechanisms that establish these states; and (b) gene regulatory circuits associated with these sex-dependent chromatin states, through which the temporal pattern of pituitary growth hormone secretion either masculinizes (pulsatile hormone stimulation) or, alternatively, feminizes gene expression in the liver (persistent hormone stimulation).

Epigenomic actions of environmental xenoestrogens – This project investigates the genomic and epigenetic actions of environmental chemicals that induce reproductive toxicities in humans and exposed wildlife. Fetal and perinatal exposure to estrogen-like chemicals can induce major structural and functional abnormalities in sensitive reproductive tissues leading to decreased fertility and adult onset of disease, including cancer. However, the molecular mechanisms that underlie the early developmental lesions and that lead to developmental and reproductive defects and adult pathophysiology are only partially understood. We are presently investigating the hypothesis that in utero exposure to environmental xenoestrogens alters epigenetic marks and epigenomic states associated with permanent changes in expression of key genes controlling reproductive tissue development, and that this knowledge can be utilized to elucidate the developmental and reproductive toxicities associated with such exposures.

Cancer therapy, angiogenesis and the immune system – Recent advances in our understanding of host-tumor interactions have provided new opportunities to improve cancer treatment using drugs that target the tumor vasculature and inhibit tumor blood vessel development (angiogenesis). This project aims to develop novel, more effective approaches to combining angiogenesis inhibitors with traditional cancer chemotherapeutics, whose access to the tumor can be substantially diminished when tumor blood flow is interdicted by anti-angiogenesis. Other goals include the use of regular, ‘metronomic’ drug delivery schedules to elicit persistent DNA damage leading to activation of a potent, anti-tumor innate immune response, and elucidation of the role of cancer stem cells (tumor-initiating cells) in cancer development, angiogenesis, and drug responsiveness.

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