The TGF-ß/SMAD signaling network plays an important role in growth inhibition of normal epithelia. In neoplastic processes, genetic and epigenetic losses of TGF-ß/SMAD signaling can result in outgrowth and invasion of transformed cells. In ovarian cancer, it has recently been reported that TGF-ß/SMAD signaling can become non-responsive to activators of TGF-ß, despite the fact that upstream regulators, such as TßRII, remain genetically intact and functional. Thus, it appears that other aberrant events, perhaps affecting co-activators or co-repressors of this growth inhibitory pathway, trigger epigenetic perturbations in TGF-ß/SMAD downstream targets.

We use computational tools to identify putative TGF-ß/SMAD target sequences and determine their functional relationship with local chromatin structure in ovarian epithelia. A novel microarray-based ChIP-on-chip assay has been developed to experimentally determine whether chromatin remodeling (i.e., histone modifications) of these predicted promoters occurs in ovarian cancer. Statistical approaches are utilized to model the interaction between SMAD complexes and altered chromatin structure and to define unique epigenetic signatures in ovarian cancer cells. Specifically, we are responsible for: 1) the development of KbTSMAD (Knowledgebase of TGF-ß/SMAD signaling pathway), an information resource of the TGF-ß/SMAD signaling pathway and its direct target gene promoters; 2) determine profiles of chromatin remodeling in these downstream loci in ovarian cancer cells; and 3) develop statistical approaches for modeling the synergistic interaction between TGF-ß/SMAD complex and altered chromatin structure and for defining unique epigenetic signatures in ovarian cancer cells.

Ramana Davuluri, Principle Investigator
Joel Saltz, Co-Investigator
Tim Huang, Co-Investigator
Michael Chan, Postdoctoral Fellow
Terry Camerlengo, Postdoctoral Fellow
Greg A. Singer, Postdoctoral Fellow
Huaxia Qin, Postdoctoral Fellow
Joseph Liu, Research Specialist

Relevant Publications:

• Victor X Jin, Gregory AC Singer, Francisco J Agosto-Pérez, Sandya Liyanarachchi and Ramana V Davuluri
  Genome-wide analysis of core promoter elements from conserved human and mouse orthologous pairs
  BMC Bioinformatics. 2006 March 23, 7:114
• Alfred S.L. Cheng, Victor X. Jin, Meiyun Fan, Laura T. Smith, Sandya Liyanarachchi, Pearlly S. Yan, Yu-Wei Leu, Michael W.Y. Chan, Christoph Plass, Kenneth P. Nephew, Ramana V. Davuluri, and Tim H.-M. Huang
  Combinatorial Analysis of Transcription Factor Partners Reveals Recruitment of c-MYC to Estrogen Receptor-a Responsive Promoters.
  Molecular Cell. 2006 February 3, 21:393-404