- PhD, University of Notre Dame
- Postdoc, University of Massachusetts Medical School
- Assistant Professor, Biochemistry and Molecular Genetics
- Phone: (434)982-6441
- Email: email@example.com
Epigenetic Silencing Mechanisms-Implications in Breast Cancer and Rett Syndrome
We are interested in understanding the regulation of gene expression by epigenetic modifications. Alterations in epigenetic regulation contribute to a number of developmental anomalies, genetic disorders and diseases, including cancer. Therefore, a detailed understanding of the mechanisms involved in epigenetic silencing is expected to shed light on these human disease states and suggest new therapeutic approaches. To pursue these interests, we use transcription-based approaches, functional screens and genomic approaches to identify new genes and regulatory pathways involved in disease initiation and progression. The projects in the lab are summarized below:
(1) Oncogenic TRIM37 as a Therapeutic Target for Breast Cancer TRIM37 is located in the 17q23 chromosomal region, which is amplified in up to ~40% of breast cancers. We demonstrated that TRIM37 functions as a H2A E3 ubiquitin ligase that mono-ubiquitinates histone H2A at lysine 119, a chromatin modification associated with transcriptional repression. Genome-wide chromatin immunoprecipitation (ChIP)-chip experiments in 17q23-amplified breast cancer cells identified many genes, including multiple tumor suppressors. We showed that TRIM37, along with PRC2 and PRC1 are co-bound to specific target genes resulting in their transcriptional silencing. Moreover, knockdown of TRIM37 in human breast cancer cells substantially decreases tumor growth in mouse xenografts. We believe that TRIM37 is an important biomarker and an attractive target for breast cancer therapeutics. To target TRIM37 for breast cancer therapeutics, we are investigating the determinant(s) of TRIM37 selective recruitment to tumor suppressors leading to their silencing.
(2) Reactivation of the Inactive X-Linked MECP2 Gene as a Therapeutic Strategy for Rett Syndrome Mammalian X chromosome inactivation (XCI) is an epigenetic process to silence the extra X chromosome in the female. We have identified several trans-acting XCI factors (XCIFs) through large-scale RNA interference screen. Interfering with the function of these XCIFs either by shRNA or small molecule inhibitors reactivated the silent X chromosome in mouse fibroblasts, differentiated embryonic stem cells and fibroblast cell line derived from a RTT patient. The reversal of XCI is therapeutically relevant to many X-linked diseases specifically to Rett Syndrome (RTT). RTT is an autism spectrum disorder affecting 1 in 10,000 girls that is caused by a defective copy of MECP2 gene. We want to develop the reversal of XCI as a therapy of RTT by reactivating the endogenous wild-type copy of MECP2 on the silenced X chromosome. We are interested in testing small molecule drugs that can reactivate the Xi-linked MECP2 gene, in vitro and in vivo.
A postdoctoral position is available to study in the laboratory immediately.
- Przanowski P, Wasko U, Zheng Z, Yu J, Sherman R, Zhu L, McConnell M, Tushir-Singh J, Green M, Bhatnagar S. Pharmacological reactivation of inactive X-linked Mecp2 in cerebral cortical neurons of living mice. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(31): 7991-7996. PMID: 30012595 | PMCID: PMC6077728
- Shivange G, Urbanek K, Przanowski P, Perry J, Jones J, Haggart R, Kostka C, Patki T, Stelow E, Petrova Y, Llaneza D, Mayo M, Ravichandran K, Landen C, Bhatnagar S, Tushir-Singh J. A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer. Cancer cell. 2018;34(2): 331-345.e11. PMID: 30107179
- Venkatesan A, Vyas R, Gramann A, Dresser K, Gujja S, Bhatnagar S, Chhangawala S, Gomes C, Xi H, Lian C, Houvras Y, Edwards Y, Deng A, Green M, Ceol C. Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma. The Journal of clinical investigation. 2017;128(1): 294-308. PMID: 29202482
- Tushir-Singh J, Bhatnagar S. In Vitro Assay to Study Histone Ubiquitination During Transcriptional Regulation. Methods in molecular biology (Clifton, N.J.). 2016;1507 235-244. PMID: 27832544
- Bhatnagar S, Green M. TRIMming down tumor suppressors in breast cancer. Cell cycle (Georgetown, Tex.). 2015;14(9): 1345-6. PMID: 25790001
- Bhatnagar S, Gazin C, Chamberlain L, Ou J, Zhu X, Tushir J, Virbasius C, Lin L, Zhu L, Wajapeyee N, Green M. TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein. Nature. 2014;516(7529): 116-20. PMID: 25470042 | PMCID: PMC4269325
- Bhatnagar S, Zhu X, Ou J, Lin L, Chamberlain L, Zhu L, Wajapeyee N, Green M. Genetic and pharmacological reactivation of the mammalian inactive X chromosome. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(35): 12591-8. PMID: 25136103 | PMCID: PMC4156765
- Schorey J, Bhatnagar S. Exosome function: from tumor immunology to pathogen biology. Traffic (Copenhagen, Denmark). 2008;9(6): 871-81. PMID: 18331451 | PMCID: PMC3636814
- Bhatnagar S, Schorey J. Exosomes released from infected macrophages contain Mycobacterium avium glycopeptidolipids and are proinflammatory. The Journal of biological chemistry. 2007;282(35): 25779-89. PMID: 17591775 | PMCID: PMC3636815
- Bhatnagar S, Shinagawa K, Castellino F, Schorey J. Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood. 2007;110(9): 3234-44. PMID: 17666571 | PMCID: PMC2200902
- Bhatnagar S, Schorey J. Elevated mitogen-activated protein kinase signalling and increased macrophage activation in cells infected with a glycopeptidolipid-deficient Mycobacterium avium. Cellular microbiology. 2005;8(1): 85-96. PMID: 16367868
- Krzywinska E, Bhatnagar S, Sweet L, Chatterjee D, Schorey J. Mycobacterium avium 104 deleted of the methyltransferase D gene by allelic replacement lacks serotype-specific glycopeptidolipids and shows attenuated virulence in mice. Molecular microbiology. 2005;56(5): 1262-73. PMID: 15882419