Dr. Denisenko's lab is interested in the mechanisms that control gene expression during organism development and aging. Chromatin, as a complex of DNA with histones and other proteins, plays an essential role in formation and long-term maintenance of stable gene expression states. Transcribed genes reside within the easily accessible euchromatin, whereas repressed genes are localized within the structurally compact heterochromatin. Transitions between chromatin states represent epigenetic level of gene expression control. To facilitate chromatin studies, Dr. Denisenko's lab developed novel technology, Matrix ChIP. To facilitate epigenetic studies in vivo, especially in animal tissues composed of multiple cells types, they have also established a novel technology for visualizing epigenetic marks at specific genomic sites in individual cells.
In a rat model, the lab found that histone modifications are altered at many genes in aging kidneys. These changes are associated with loss of silencing and ectopic expression of collagen and laminin genes that contribute to the development of aging nephropathy. Lab is looking for changes in histone modifications and relevant enzymes that cause gene dysregulation during aging. Contribution of these epigenetic changes to hyper-reactive inflammatory responses associated with old age is examined in model systems.
Studies carried out in animal models and humans demonstrated that poor intrauterine environment slows fetal growth (intra-uterine growth restriction, IUGR), causes low birth weight, increases risk of developing chronic diseases, and decreases life span. In animal models, the Denisenko lab found that two major causes of fetal undernutrition in humans, maternal dietary restriction (microswine and mice) and placental insufficiency (sheep), both trigger global downregulation of transcription in fetal tissues. Switch to a normal diet after birth results in increased global transcription rates in these animals compared to control animals. It means that poor intrauterine environment programs transcription response that persists after birth. This programing involves epigenetic mechanisms because altered transcription rates are matched by changes in DNA methylation in these animals. The fact that malnutrition during periconceptional period only is sufficient for such programing, defines early stages of embryo development as the most sensitive to nutrition period. Changes in transcription rates can promote unbalanced growth of the offspring and increased risk of chronic diseases. It defines global transcriptional rates as a plausible mediator of future health and/or disease and as a target for interventions to protect against chronic diseases
Nelson JD, Denisenko O, Bomsztyk K. Protocol for fast chromatin immunoprecipitation (ChIP) method. Nature Protocols. 2006; 1(1): 179-85.
• PubMed Abstract
Abrass CK, Hansen H, Popov V, Denisenko O. Alterations in chromatin are associated with increases in collagen III expression in aging nephropathy. Am J Physiol Renal Physiol. 2011; 300(2): F531-9.
• PubMed Abstract
Denisenko O, Lin B, Louey S, Thornburg K, Bomsztyk K, Bagby S. Maternal malnutrition and placental insufficiency induce global downregulation of gene expression in fetal kidneys. J Develop Origins Health Dis. 2011; 2(2): 124-33.
• Cambridge Journals Abstract
Bomsztyk K, Denisenko O. Epigenetic alterations in acute kidney injury. Semin Nephrol. 2013; in press.
Giacani L, Denisenko O, Tompa M, Centurion-Lara A. Identification of the Treponema pallidum subsp. pallidum TP0092 (RpoE) Regulon: implications for pathogen persistence in the host and syphilis pathogenesis. J Bac, 195(4):896-907, 2013
• PubMed Abstract