Chakravarti Lab

One of Chakravarti's major research interests is to determine the mechanisms of steroid hormone and vitamin signaling with special emphasis on the role of the nuclear hormone receptor co-regulatory proteins in gene transcription. Modulation of chromatin modification is essential for gene expression and therefore its alteration has been linked to human diseases including cancer.

Chakravarti's laboratory identifies and characterizes the role of chromatin signal transducer proteins including the recently identified INHAT proteins in gene regulation. The lab is also characterizing members of a novel THAP domain protein family regarding their roles in gene regulation, chromatin signaling, cell growth and differentiation and cancer.

Members of the Chakravarti Lab in the Division of Reproductive Science in Medicine in the Department of Obstetrics & Gynecology have continued to make key and dogma-changing discoveries that push the boundary of current knowledge on transcriptional, hormonal and epigenetic regulation of cell cycle progression, uterine biology (fibroids or leiomyoma) and tumorigenesis (MCB, 2012, editor’s pick paper, Cell Reports, 2014, MCB Dec 2015, spotlight paper, Mol. Cell 2009, Mol. Cell 2014, Mol. Endo 2013, 2016). 

1. Nuclear receptor and epigenomic regulation of Uterine Fibroids (Mol. Endo, 2013): We focused on a major health problem termed uterine fibrosis or leiomyoma, which still to this day remains poorly understood. We have identified key nuclear receptors that influence leiomyoma. This work is highly influential because based on our work similar analysis in other diseases including liver, lung, kidney, breast and cardiac fibrosis will be carried out advancing our understanding of fibrotic diseases and opening up new therapeutic approaches. We are currently determining genome-wide epigenomic and transcription factor signatures that define uterine fibrosis.
2.  Epigenetics, chromatin dynamics and human cancers (Mol. Cell 2009, Mol. Cell 2014, MCB 1011, Mol. Endo, 2016): Our knowledge of the role of histone phosphorylation as an epigenomic regulator of physiology is limited. Using biochemical, molecular and cellular analyses, we demonstrated that histone H3 serine 10 phosphorylation functions as a module that promotes release of key cellular proteins such as SRp20, and heterochromatin protein HP1. These studies are important because they identify these proteins as key transducers of chromatin signaling during cell cycle progression. We also identified a WD repeat protein WDR5, which is a key subunit of the MLL/Set1 histone methyltransferase complex, as a transducer of histone H3 threonine 11 phosphorylation in prostate cancer cells. Our extensive molecular and genome wide studies as well as analysis of human cancer samples suggest that WDR5-H3T11P interaction integrates epigenetic cross talk in driving androgen receptor target gene expression, prostate cancer cell proliferation and disease progression.  These studies will promote future investigations on the role of histone phosphorylation in other human cancers.
3. Characterization of new family of transcription factors and Transcriptional control of cell cycle genes: There is a large family of novel Zn-finger transcription factors that remained primarily uncharacterized. We, in a dogma changing study demonstrated that key cell cycle genes are regulated by HCFC1 cofactor recruitment not by the E2F proteins but by a THAP11-ZNF143 transcriptional complex. These studies are highly significant because it changes the paradigm that E2F mediated HCFC1 recruitment is critical for expression of cell cycle target genes, and raises the possibility that E2F participates in this process by recruiting factors other than HCFC1, thereby promoting new directions of research in this highly active field. Secondly, our effort will stimulate future research on further characterization of all THAP domain proteins.

• Seo, S-B., McNamara, P., Heo, S., Turner, A., Lane, W.S., and Chakravarti, D. Regulation of histone acetylation and transcription by INHAT, a novel human cellular complex containing the Set oncoprotein. Cell 104: 119-130, 2001.
• McNamara, P., Seo, S-B, Rudic, R.D., Sehgal, A., Chakravarti, D., and FitzGerald, G.A. Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: A humoral mechanism to reset a peripheral clock. Cell 105, 877-889, 2001.
• Li, F, Macfarlan, T., Pittman, R.N., and Chakravarti, D. Ataxin-3 is a histone binding protein with two independent transcriptional corepressor activities, J. Biol. Chem. 277: 45004-45012, 2002.
• Hong, R., and Chakravarti, D. The human proliferating cell nuclear antigen regulates transcriptional coactivator p300 activity and promotes transcriptional repression. J. Biol. Chem. 278: 44505-44513, 2003.
• Chakravarti D. and Hong, R. SET-ting the stage for life and death. Cell 112: 589-591, 2003.
• Kutney S.N., Hong, R., Macfarlan, T., and Chakravarti, D. A signaling role of histone-binding proteins and INHAT subunits pp32 and Set/TAF-I beta in chromatin hypoacetylation and transcriptional repression. J.Biol. Chem. 279: 30850-30855, 2004.
• Hong, R., Macfarlan, T., Kutney, S.N., Seo, S.B., Mukai, Y., Yelin F., Pasternack, G.R. and Chakravarti, D. The identification of phosphorylation sites of pp32 and biochemical purification of a Cellular pp32-kinase. Biochemistry. 43, 10157-10165, 2004.
• Macfarlan, T., Kutney, S., Altman, B., Montross, R., Yu, J., and Chakravarti, D. Human THAP7 is a chromatin-associated, histone tail binding protein that represses transcription via recruitment of HDAC3 and nuclear receptor corepressor. J.Biol. Chem. 280, 7346-7358, 2005
• Macfarlan, T., Parker, J.B., Nagata, K., and Chakravarti, D. Thanatos-associated protein 7 associates with template activating factor –Ibeta and inhibits histone acetylation to repress transcription. Mol.Endo (in press) Feb, 2006.