Our Major Research Interests
The major direction in our research is to establish the mechanisms that operate in the expression process of genetic information in biological systems. We are particularly interested in the regulation of gene expression at the level of DNA transcription. We search for links between coherent localized dynamics of DNA that may prove to be a major determinant of DNA functions such as the initiation of gene transcription. We search for links between control of gene expression and metabolic status. We search for the potential role of acetylation and O-glycosylation of transcription factors as metabolic sensors in the modulation of gene expression patterns both, acutely and chronically in diabetes and aging. 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.
DNA participates in directing its transcription through structurally specific dynamics.
Recently we illustrated coherent localized dynamics of DNA that may prove to be a major determinant of DNA functions such as the initiation of gene transcription. We demonstrated that structurally specific coherent thermal fluctuations identify locations in the DNA sequences where the RNA polymerases initiate transcription. Further, we discovered indications that the thermal fluctuations help in recruiting other protein complexes participating in the transcriptional process by DNA double strand distortion at specific locations. Our observations suggest that DNA participates in directing its transcription through structurally specific dynamics.
Basic transcription may be linked to fatty-acid synthesis, cellular respiration and metabolic state.
Post-translational modifications of transcription factors such as acetylation play an important regulatory function by acting as switches of activity. Recently we discovered a new autoenzymatic acetylation activity in the general transcription factor IIB (TFIIB), a protein required for eukaryotic polymerase II transcription. Our finding suggests a new view of the role and importance of acetylation in transcription - the potential self-regulation of core promoter activity and its dependence on acetyl-TFIIB. As acetyl-CoA is an important cofactor in this reaction, this finding demonstrates that basic transcription may be linked to fatty-acid synthesis and cellular respiration. The implications of such connections would be far-reaching in cellular biology. We propose that the acetylation of TFIIB is capable of regulating transcription in response to fasting and aging. This would establish a novel role for acetyl-CoA as a metabolic regulator of transcription.
Recently we reported that the multifunctional transcription factor YY1 is O-glycosylated and this modification functions as YY1-specific sensor of the cellular metabolic status. O-GlcNAcylation is a protein modification on serine or threonine residues with thea monosaccharide N-acetylglucosamine, in an O-glycosidic linkage. We are particularly interested in determining whether O-GlcNAcylation of YY1 regulates YY1-Rb/Notch interactions and downstream gene transcription leading to triggering of vascular response to injury and atherosclerosis in hyperglycemic conditions.
In animal and humans, mRNA expression and gene expression can dramatically change following organ transplantation. In collaboration with Dr. Fritz Bach at BIDMC, we are searching for markers which may predict rejection of a transplanted organ.
For a listing of Dr. Usheva's laboratory publications,