Inez Rogatsky, PhD

Appointments

Assistant Scientist, Hospital for Special Surgery

Assistant Professor, Department of Microbiology and Immunology, Weill Medical College of Cornell University

Member, Graduate Program in Immunology and Microbial Pathogenesis, Weill-Cornell

Member, Allied Graduate Program in Biochemistry, Cell and Molecular Biology (BCMB), Weill-Cornell

 

Selected Publications

Rogatsky I., Zarember K.A. and Yamamoto K.R. (2001) Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. EMBO J. 20:6071-83.

Rogatsky I., Luecke H.F., Leitman D.C. and Yamamoto K.R. (2002) Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts. Proc. Natl. Acad. Sci. USA, 99:16701-6.

Rogatsky I., Wang J.-C., Derynck M.K., Nonaka D.F., Khodabakhsh D.B., Haqq C.M., Darimont B.D., Garabedian M.J. and Yamamoto K.R. (2003) Target-specific utilization of transcriptional regulatory surfaces by the glucocorticoid receptor. Proc. Natl. Acad. Sci. USA, 100:13845-50.

Chen W., Rogatsky I. and Garabedian M.J. (2006) MED14 and MED1 differentially regulate target-specific gene activation by the glucocorticoid receptor. Mol. Endocrinol. 20:560-72.

Reily M.M., Pantoja C., Hu X., Chinenov Y. and Rogatsky I. (2006) The GRIP1:IRF3 interaction as a target for glucocorticoid receptor-mediated immunosuppression. EMBO J. 25:108-17.

Takayama S., Rogatsky I., Schwarcz L.E., Darimont B.D. (2006) The glucocorticoid receptor represses cyclin D1 by targeting the Tcf-#-Catenin complex. J. Biol. Chem. 281:17856-63.

Rogatsky I. and Ivashkiv L.B. (2006) Glucocorticoid modulation of cytokine signalling. Tissue Antigens, 68:1-12.

Chinenov Y. and Rogatsky I. (2007) Glucocorticoids and the innate immune system: Crosstalk with the Toll-like receptor signaling network. Mol. Cell. Endocrinol. 275:30-42.

Chen W., Dang T., Blind R., Wang Z., Cavasotto N.C., Hittelman A., Rogatsky I., Logan S.K. and Garabedian M.J. (2008) Glucocorticoid receptor phosphorylation differentially affects target gene expression. Mol. Endocrinol. 22:1754-66.

Chinenov Y., Sacta M.A., Cruz A.R., Rogatsky I. (2008) GRIP1-associated SET-domain methyltransferase in glucocorticoid receptor target gene expression. Proc. Natl. Acad. Sci. USA 105: 20185-90.

For more publications, please see the PubMed listing.  

Research Description

Transcriptional Cross-talk Between Glucocorticoids and the Immune System

Glucocorticoid hormones (GC) are potent natural immunosuppressors, which interfere with the immune system function both by inducing apoptosis in many white blood cells of lymphoid and myeloid origin, and by suppressing the production of numerous cytokines, chemokines and other mediators of inflammation, thereby disrupting communication between the immune cells. Not surprisingly, GCs have been used for decades to combat inflammatory, autoimmune and lymphoproliferative diseases. Our goals are to understand the molecular mechanisms, cofactors and targets of GCs and their role in inflammation, cell proliferation and immune response.

GCs signal through the intracellular glucocortcoid receptor (GR), a ligand-dependent transcription factor of the nuclear receptor family. Upon exposure to hormone, GR translocates to the nucleus, binds to palindromic glucocorticoid response elements (GREs) on DNA and activates or represses a wide variety of genes. In addition to binding DNA directly, GR can ‘tether’ to other DNA-bound transcription factors through protein:protein interactions, typically repressing their activities. For example, GR-dependent repression of AP-1 and NF-kB accounts for many immunosuppressive effects of GCs, yet, the molecular mechanisms of repression are not well understood. Furthermore, the broad actions of GCs on the immune system likely involve additional transcriptional regulators, but their identity is unknown.

We found that GRIP1, a member of the p160 family of coactivators, serves as a specific GR ligand-dependent corepressor at the AP-1 and NF-kB sites. This activity is mediated by a unique GRIP1 corepression domain (RD), which does not resemble any known protein. In a yeast 2-hybrid screen for RD-interacting factors, we isolated Interferon Regulatory Factor (IRF)-3, an essential component of the innate immune system downstream of TLRs 3/4 responsible for the production of type I interferon and several other cytokines and chemokines. Our studies revealed an unexpected link between the GR and IRF3 signaling pathways, identifying IRF3 is a previously unrecognized target for GC-mediated immunosuppression and GRIP1 as a novel coregulator of innate immunity. Furthermore, the interferon signaling pathway itself appeared to be under GR control and we are investigating which step in the interferon-JAK/STAT cascade is GC-sensitive.

Another factor isolated in the screen was a novel protein later shown to be an inhibitory histone methyltransferase (HMTase) Suv4-20, which specifically tri-methylates histone H4 lysine 20. This modification is a marker for constitutive heterochromatin and, accordingly, Suv4-20 associates with transcriptionally silent domains. Unexpectedly, we found that Suv4-20 actively participates in hormone-dependent transcriptional regulation as a GRIP1-associated cofactor for a subset of GR target genes including known suppressors of inflammatory response.

We use biochemical, molecular, cell-based and in vivo approaches to identify points of cross-talk between the GCs and the pathways mediating inflammation, autoimmunity and uncontrolled cell proliferation. Understanding the major players and mechanisms of such interactions is essential for developing more specific therapies.