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 structural 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. It has also established a novel technology for visualizing epigenetic marks at specific genomic sites in individual cells that will advance epigenetic studies in vivo, especially in animal tissues composed of multiple cells types.
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. Looking for histone modifying enzymes involved in these processes, the lab found that dysbalance between PRC2 and KDM6 activities account for the loss of gene silencing with aging.
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. The lab also examined animals born to malnourished mothers. To mimic conditions present in human societies in developing countries, these animals were fed normal diet after birth. Strikingly, global transcription rates were increased in these animals compared to normal control animals. The Denisenko lab proposes that in poor environment, the fetus develops a protective (thrifty) transcriptional response that persists after birth and increases chances of survival and mating competitiveness of the offspring. However, as environmental circumstances improve, the organism switches from poor to normal diet, the same adaptive mechanisms will result in higher than normal transcription rates, promoting accelerated unbalanced growth of the offspring and increased risk of chronic diseases. It means that interventions to protect against disease should be targeted at tuning global transcriptional rates as an upstream mediator of future health and/or disease.
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.