The major purpose of our research is to establish the mechanisms that operate in the expression process of genetic information in biological systems. We search for links between control of gene expression and cellular metabolic status. We search for the potential role of protein acetylation and glycosylation in the modulation of gene expression patterns both acutely - in terms of food restriction - and chronically in ovarian aging. We are particularly interested in the regulation of gene expression at the level of DNA transcription. We approach it at four different levels - at the electronic and thermodynamic levels, at the molecular level, and at the cellular and mammalian tissue levels.
1. Links between control of gene expression at the level of transcription core promoter activity and cellular metabolic status. The long-term objective of this project is to understand the relationship between acetylation and O-linked N-acetylglucosaminylation (O-GlcNAcylation) of transcription factors and gene promoter regulation. Several transcription factors have been found to be acetylated and N-acetylglucosaminylated. Researchers are now faced with the challenge of learning how these modifications work. This progect is a biochemical approach to the analysis of the human basic transcription factor IIB auto-acetylation and transcription factor YY1O- GlcNAcylation to provide a better understanding of how this posttranslational modifications link basic gene transcription to fatty-acid synthesis and cellular energy metabolism.
2. Transcription factor YY1 functions in regulation of vascular responce to injury.The proliferating smooth muscle cells in the vascular neointima express significantly more YY1 compared to the none proliferating smooth muscle cells in healthy vessels. Our hypothesis is that YY1 O-GlcNAcylation, regulating the YY1-Rb interaction and downstream transcription, together with the elevated amount of YY1 in response to injury, promotes neointimal formation. Our goal is to study the YY1 participation in transcriptional pathways that operate in the vascular responce to injury.
3. We are particularly interested in the molecular mechanisms that underlie the decline in human oocyte fertility competence with aging. In collaboration with Boston IVF we search for molecular markers of infertility in human ovarian follicular fluids. We propose that changes in the follicular cholesterol composition and trafficking is likely to play a role in the maturation of fertility competent human oocytes.
4. Gene Promoter Prediction Using the probability of DNA for strand separation. The field of promoter prediction holds almost limitless potential, but has had very limited success. Instead of analyzing DNA sequence homology, we are developing a novel method of eucaryotic promoter prediction based on the physical properties of DNA, which arise from the local sequence. Using computer simulations with a nonlinear mathematical model, we predict the localized opening profile of a region of genomic DNA. By Dielectric and THz spectroscopy, NMR and adiabatic calorimetry we search for promoter-specific electronic features of DNA. Using computational simulation we are determining patterns of high probability double strand distortion profiles of known promoters. We are applying the method for promoter prediction of known genes with unknown promoters for further validation of the computational simlation.
5. Transcription regulation of ovarian aging, ovarian infertility, and menopausal transition.
Zimon A, Erat A, Von Wald T, Bissell B, Koulova A, Choi CH, Bachvarov D, Reindollar RH, Usheva A. Genes invoked in the ovarian transition to menopause.Nucleic Acids Res. 2006 Jun 28;34(11):3279-87
Choi CH, Kalosakas G, Rasmussen KO, Hiromura M, Bishop AR, Usheva A. DNA dynamically directs its own transcription initiation. Nucleic Acids Res. 2004 Mar 5;32(4):1584-90
Petkova V, Romanowski MJ, Sulijoadikusumo I, Rohne D, Kang P, Shenk T, Usheva A. Interaction between YY1 and the retinoblastoma protein. Regulation of cell cycle progression in differentiated cells J Biol Chem 2001 Mar 16;276(11):7932-6
Usheva A, Shenk T. TATA-binding protein-independent initiation: YY1, TFIIB, and RNA polymerase II direct basal transcription on supercoiled template DNA.Cell 1994 Mar 25;76(6):1115-21
Choi CH, Hiromura M, Usheva A. Transcription factor IIB acetylates itself to regulate transcription. Nature 2003;424(6951):965-9.
External Recognition:
2005 - Electronic features of DNA, invited lecturer at the international physics summer school in Eriche, Italy.
2005 - Basic mechanisms of gene transcription regulation - Los Alamos National Laboratory, Invited Lecturer
2005 - Hawaii Physics workshop, invited lecturer
2004 - Transcription response to endothelin and glucose in coronary artery smooth muscle cells – LaVall University, Quebec, Canada, Invited Lecturer
Major Collaborative Activities:
YY1 functions in atherosclerosis– collaborative studies with Dr. Simon Robson, Department of Surgery, Beth Israel Deaconess Medical Center.
Electronic features of the basic transcription complex - Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Materials Research and Engineering Center, Harvard University
