David J. Waxman, Ph.D.
Professor, (Biology, Medicine, BME)
Professor, (Biology, Medicine, BME)
- Primary Appointment Professor, Biology
- Education Ph.D., Biochemistry & Molecular Biology, Harvard University
B.A., Chemistry, Queens College, CUNY
- Additional Affiliations Professor, Medicine
Professor, Biomedical Engineering
- Areas of Interest Genomic and epigenetic mechanisms controlling liver gene expression; molecular endocrinology and cell signaling through transcriptional networks; nuclear receptors and responses to environmental chemicals; role of immune system in cancer therapy and pharmacology.
Our research program encompasses the following three major questions:
1) How do hormone regulatory circuits and the epigenomic events that they activate regulate complex patterns of gene expression in mammalian tissues?
2) By which mechanisms do environmental chemicals reprogram postnatal gene expression, inducing metabolic dysregulation and impaired reproductive function?
3) Can improved strategies for cancer treatment be devised through a better understanding of the impact of cancer chemotherapy on host-tumor interactions affecting immune responses to cancer therapy?
- Research Areas Hormone regulation of sex differences in liver gene expression – This project aims to elucidate genome-wide transcriptional and epigenetic networks that control 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, which identifies open chromatin regions in the genome (DNase-seq), chromatin state analysis (DNA methylation, histone marks), chromatin conformation capture (4C), and RNA interaction analysis (RIP-seq). These rich, genome wide data sets are being used to identify: (a) the unique chromatin states that characterize genes showing sex differences in their expression, and the mechanisms and epigenetic events that establish these states; and (b) gene regulatory circuits and long-range chromatin looping interactions associated with 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 interact with nuclear receptors and induce metabolic dysregulation and reproductive toxicities in humans and exposed wildlife. Fetal and perinatal exposure to estrogen-like chemicals can induce major structural and functional abnormalities in sensitive tissues leading to decreased fertility and adult onset of disease, including cancer. However, the molecular mechanisms that underlie the early developmental and other lesions that lead to adult pathophysiology are only partially understood. We are currently investigating the hypothesis that exposure to xenoestrogens and other environmental chemicals alters epigenetic marks and chromatin states linked to permanent changes in expression of genes with key metabolic and reproductive tissue functions.
Cancer therapy and the immune system – Recent advances in our understanding of host-tumor cell interactions provide new opportunities to improve cancer treatment using drugs that modulate immune responses. Focusing on glioblastoma, we aim to develop novel, more effective therapies based on traditional cancer chemotherapeutics combined with treatments that target the immune system. In one approach, we are using ‘metronomic’ drug delivery schedules that elicit persistent DNA damage and can activate immunogenic cell death. Our studies are designed to elucidate underlying pathways and mechanisms of drug-induced immune responses, and to identify factors that can be translated into the clinic to help distinguish immune responsive from immune unresponsive tumors and patients.
Select Recent Publications
- Matthews BJ, Waxman DJ (2018) Computational prediction of CTCF/cohesin-based intra-TAD loops that insulate chromatin contacts and gene expression in mouse liver. Elife. PII: e34077. DOI: 10.7554/eLife.34077. PubMed PMID: 29757144.
- Lodato NJ, Rampersaud A, Waxman DJ (2018) Impact of CAR agonist ligand TCPOBOP on mouse liver chromatin accessibility. Toxicol Sci. DOI: 10.1093/toxsci/kfy070. PubMed PMID: 29617930.
- Wu J, Waxman DJ (2018) Immunogenic chemotherapy: Dose and schedule dependence and combination with immunotherapy. Cancer Lett. 419: 210-221. DOI: 10.1016/j.canlet.2018.01.050. PubMed PMID: 29414305.
- Hao P, Waxman DJ (2018) Functional Roles of Sex-Biased, Growth Hormone-Regulated MicroRNAs miR-1948 and miR-802 in Young Adult Mouse Liver. Endocrinology 159(3): 1377-1392. DOI: 10.1210/en.2017-03109. PubMed PMID: 29346554.
- Lodato NJ, Melia T, Rampersaud A, Waxman DJ (2017) Sex-Differential Responses of Tumor Promotion-Associated Genes and Dysregulation of Novel Long Noncoding RNAs in Constitutive Androstane Receptor-Activated Mouse Liver. Toxicol Sci. 159(1): 25-41. DOI: 10.1093/toxsci/kfx114. PubMed PMID: 28903501.
- Lau-Corona D, Suvorov A, Waxman DJ (2017) Feminization of male mouse liver by persistent growth hormone stimulation: Activation of sex-biased transcriptional networks and dynamic changes in chromatin states. Mol Cell Biol. 2017 Jul 10. PII: MCB.00301-17. DOI: 10.1128/MCB.00301-17. PubMed PMID: 28694329.
- Connerney J, Lau-Corona D, Rampersaud A, Waxman DJ (2017) Activation of male liver chromatin accessibility and STAT5-dependent gene transcription by plasma growth hormone pulses. Endocrinology DOI: 10.1210/en.2017-00060. PubMed PMID: 28323953.
- Wu J, Jordan M, Waxman DJ (2016) Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators. BMC Cancer 16:623. DOI: 10.1186/s12885-016-2597-2. PubMed PMID: 27515027; PubMed Central PMCID: PMC4982114.