Inez Rogatsky, PhD

Selected Publications

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.

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. 

Adelman K., Kennedy M.A., Nechaev S., Gilchrist D.A., Muse G.W.,Chinenov Y., Rogatsky I. (2009) Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase II stalling. Proc. Natl. Acad. Sci. USA 106:18207-12.

Flammer J.R., Dobrovolna J., Kennedy M.A., Chinenov Y., Glass C.K., Ivashkiv L.B., Rogatsky I. (2010) Type I interferon signaling pathway is a target for glucocorticoid inhibition. Mol. Cell. Biol. 30: 4564-4574 Supplementary Material

Flammer J.R. and Rogatsky I. (2011) Glucocorticoids in autoimmunity: unexpected targets and mechanisms. Mol. Endocrinol. 7: 1075-86

Dobrovolna J., Chinenov Y., Kennedy M.A., Liu B. and Rogatsky I. (2012) Glucocorticoid-dependent phosphorylation of the transcriptional coregulator GRIP1. Mol. Cell. Biol. 32:730-9

Chinenov Y., Gupte R., Dobrovolna J., Flammer J.R., Liu B., Michelassi F.E. and Rogatsky I. (2012) The role of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids. Proc. Natl. Acad. Sci. USA 109:11776-81

Chinenov Y., Gupte R. and Rogatsky I. (2013) Nuclear receptors in inflammation control: repression by GR and beyond. Mol. Cell. Endocrinol. 380:55-64
 

Gupte R., Muse G.W., Chinenov Y., Adelman K. and Rogatsky I. (2013) Glucocorticoid receptor represses pro-inflammatory genes at distinct steps of the transcription cycle. Proc. Natl. Acad. Sci. USA 110:14616-21

Rogatsky I. and Adelman K. (2014) Preparing the first responders: Building the inflammatory transcriptome from the ground up. Molecular Cell 54:245-54


 


 

For more publications, please see the PubMed listing.

Research Description

 Transcriptional Cross-talk Between Glucocorticoids and the Immune System

Glucocorticoid hormones (GCs) are potent immunosuppressors, which interfere with the immune system function by promoting lymphocyte killing, and by suppressing the production of numerous cytokines, chemokines and other mediators of inflammation. Not surprisingly, GCs have been used for decades to combat inflammatory and autoimmune diseases. At the same time, pharmacological long-term administration of GCs can cause serious side effects, particularly on metabolism (insulin resistance, type II diabetes) and on the bone (osteoporosis). Uncoupling the anti-inflammatory and side effects of these compounds requires detailed molecular understanding of their mechanisms of actions. GC signal through the intracellular glucocorticoid receptor (GR), a ligand-dependent transcription factor which upon exposure to hormone, translocates to the nucleus, binds GC response elements (GREs) on DNA and triggers the assembly of multiprotein transcriptional regulatory complexes which activate or repress a wide variety of genes. Our goals are to understand the molecular composition and mechanisms of action of these complexes, as well as the genomic targets of GR in immune cells vs. other cell types.

1. GRIP1, GR-mediated transcriptional repression and the anti-inflammatory actions of GCs.

In addition to activating transcription by binding to palindromic GREs, GR is well known to ‘tether’ to other DNA-bound transcription factors, notably AP1 and NFkB, and repress their activity. Because AP1 and NFkB are responsible for activating a variety of inflammatory cytokine and chemokine genes, repression by GR via tethering is considered a key component of the anti-inflammatory and immunosuppressive actions of GCs, however the underlying mechanisms remain obscure. Our studies revealed that GRIP1 (TIF2/NCoA2), an established transcriptional coactivator for GR at palindromic GREs, is also recruited to GR ‘tethering’ sites as a ‘non-traditional’ co-repressor. We generated a mouse strain enabling GRIP1 deletion in macrophages in adult animals. Using this genetic system, our genome-wide transcriptome analyses in WT vs GRIP1 KO macrophages revealed global desensitization of pro-inflammatory genes to GC repression which in vivo correlated with an exaggerated systemic response of the GRIP1 KO mice to inflammatory triggers such as LPS (Chinenov, Gupte et al, Proc Natl Acad Sci USA 2012). The specific molecular mechanism underlying GRIP1 corepressor function is under investigation.

2. GC repress inflammatory genes activated both at the initiation and elongation step of the transcription cycle.

Recruitment of RNA Polymerase II (Pol II) to target promoters is often the rate-limiting step for gene activation, yet in recent years, a different view has emerged. Many genes are occupied by transcriptionally engaged Pol II even prior to stimulation, however no full-length transcript is produced. Instead, Pol II pauses or stalls at the promoter-proximal region until signal-dependent phosphorylation by CDK9 dismisses the Negative Elongation Factor (NELF) complex from the promoter enabling productive elongation. We discovered that many mediators of inflammation are activated by such Pol II release from promoter-proximal stalling (Adelman et al, Proc Natl Acad Sci USA 2009). Interestingly, inflammatory genes of both classes are repressed by GR:GRIP1 complexes albeit the molecular targets of their action within components of basal transcriptional machinery appear to differ (Gupte et al, Proc Natl Acad Sci USA 2013). We seek to understand how GR:GRIP1 block Pol II recruitment at some genes and attenuate CDK9-mediated pause release at others.

3. Regulation of GRIP1 by phosphorylation.

GRIP1 is a multi-functional coregulator that can elicit opposite transcriptional responses (activation vs repression) or engage in complexes with biologically antagonistic functions, such as immunosuppression in conjunction with GR or innate immune response when bound by IRFs. What enables this regulatory diversity is unknown. Unexpectedly, we discovered that in response to GCs, GRIP1 is phosphorylated on multiple sites and by multiple kinases in a GR-interaction dependent manner, which affects its transcriptional activity (Dobrovolna et al, Mol Cell Biol 2011). Furthermore, we detect distinct GRIP1 phospho-isoforms at individual GR genomic binding sites suggesting that phosphorylation can serve as a code to drive both selective recruitment and function of GRIP1. In addition, we aim to identify posttranslational modifications that may occur in response to signals that activate non-GR GRIP1 partners (e.g., IRFs) as a potential mechanism for selectivity in GRIP1 functions in different pathways.

4. GR and GRIP1 in macrophage polarization and metabolic homeostasis.

Macrophages are a cell type of great plasticity. With the growing appreciation of the critical role of macrophage-driven chronic inflammation in many diseases, including metabolic syndrome, insulin resistance, atherosclerosis and cardiovascular disease, came the recognition that macrophage populations differ in their developmental origin and perform distinct, even opposing functions even in the same tissue. For example in obese adipose tissue during metabolic syndrome, classically activated inflammatory macrophages (M1) promote chronic inflammation aggravating insulin resistance, whereas resident alternatively-activated (M2) macrophages are anti-inflammatory, normally populate ‘lean’ adipose tissue and antagonize obesity and metabolic dysfunction. GCs are well known for their diabetogenic systemic side effects, however in macrophages, they both suppress inflammatory gene expression in M1 and promote the polarization of M2. GRIP1 participates in both processes, and our preliminary data suggest that mice conditionally lacking GRIP1 in macrophages display a metabolic phenotype. We are actively pursuing the mechanistic and physiological basis of the protective effects of the macrophage GRIP1 in the obesity-induced model of metabolic syndrome.

 

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Contact Information

Office Locations

Caspary Research Building
541 East 71st Street
New York, NY 10021

Tel: 212.606.1462
Fax: 212.774.2560

Mailing Address

Hospital for Special Surgery
535 East 70th Street
New York, New York 10021

Email Dr. Rogatsky