David J. Waxman, Ph.D.
Professor, (Biology, Medicine, BME)
- Email firstname.lastname@example.org
- Phone 617-353-7402
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
Melia T, Hao P, Yilmaz F, Waxman DJ. (2016) Hepatic lincRNAs: high promoter
conservation and dynamic, sex-dependent transcriptional regulation by growth hormone. Mol Cell Biol. 2015 Oct 12. pii: MCB.00861-15. PDF
Suvorov A, Waxman DJ. (2015) Early programing of uterine tissue by bisphenol A: Critical evaluation of evidence from animal exposure studies. Reprod Toxicol. 2015 Nov;57:59-72. Review. PubMed PMID: 26028543; PubMed Central. PDF
Conforto TL, Steinhardt GF 4th, Waxman DJ. (2015) Cross Talk Between GH-Regulated Transcription Factors HNF6 and CUX2 in Adult Mouse Liver. Mol Endocrinol. 2015 Sep;29(9):1286-302. PubMed PMID: 26218442; PubMed Central. PDF
Wu J, Waxman DJ. (2015) Metronomic cyclophosphamide eradicates large implanted GL261 gliomas by activating antitumor Cd8(+) T-cell responses and immune memory. Oncoimmunology. 2015 Feb 18;4(4):e1005521. eCollection 2015 Apr. PubMed PMID: 26137402; PubMed Central.PDF
Chen CS, Doloff JC, Waxman DJ. (2014) Intermittent metronomic drug schedule is essential for activating antitumor innate immunity and tumor xenograft regression. Neoplasia. 2014 Jan;16(1):84-96. PubMed PMID: 24563621; PubMed Central. PDF
Sugathan A, Waxman DJ. (2013) Genome-wide analysis of chromatin states reveals distinct mechanisms of sex-dependent gene regulation in male and female mouse liver. Mol Cell Biol. 2013 Sep;33(18):3594-610. PubMed PMID: 23836885; PubMed Central. PDF
Conforto TL, Zhang Y, Sherman J, Waxman DJ. (2012) Impact of CUX2 on the female mouse liver transcriptome: activation of female-biased genes and repression of male-biased genes. Mol Cell Biol. 2012 Nov;32(22):4611-27. PubMed PMID: 22966202; PubMed Central. PDF
Shao Z, Zhang Y, Yuan GC, Orkin SH, Waxman DJ. (2012) MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets. Genome Biol. 2012 Mar 16;13(3):R16. PubMed PMID: 22424423; PubMed Central. PDF