When two patients with the same disease take the same medication, they may have very different responses. One person may experience a dramatic improvement, while the other may have no change at all.
This difference may be related to how our bodies metabolize drugs. A group of enzymes known as cytochrome P450s (CYPs) are responsible for oxidizing substances in the body, including drugs.
CYP activity is responsible for how quickly a drug metabolizes, which determines the intensity and duration of the drugs’ effects in the body. CYPs are responsible for the therapeutic outcomes of 60-70% of drugs.
Scientists already know that transcription factors, a kind of protein, bind DNA elements and facilitate transcriptional regulation of CYPs by alerting histones. This opens the DNA up to be transcribed into proteins. Histone modifications are the major epigenetic elements at play in CYP gene expression.
But the question remains: how, exactly, do transcription factors trigger histone modifications and facilitate the regulation of CYP expression?
UConn professor of pharmacology and toxicology Xiaobo Zhong suspects long non-coding RNAs (lncRNAs) may be the key to answering this question.
Zhong has received a $2 million grant from the National Institutes of Health to investigate the regulatory mechanisms that control the expression of CYPs.
Only about 2% of the human genome is protein-coding genes, the majority of the genome is long or short non-coding sequences, based on if they have greater or fewer than 200 nucleotides. While they do not directly translate into a protein, these non-coding RNAs play a critical role in other cellular functions.
Understanding how the genes that code for CYPs are regulated is critical for predicting if a given drug treatment will be effective and if a patient will experience an adverse reaction.
This grant will build upon Zhong’s previous findings which determined the role of lncRNAs in drug metabolism.
Zhong has identified two lncRNAs of interest: HNF1A-AS1 and HNF4A-AS1. These lncRNAs are located near transcription factor genes HNF1A and HNF4A, which encode proteins that play an important role in regulating the CYP gene’s expression.
In addition to investigating the role these lncRNAs play in epigenetic regulation, Zhong will also determine the influence they have on individuals’ susceptibility to drug-induced liver injury, a common concern with many medications.
Zhong will test if these lncRNAs are in fact responsible for three important functions: maintaining homeostasis of CYP enzymes in the liver when they encounter a drug; influencing susceptibility to drug-induced liver injury and regeneration; and interacting with histone modifications. He will enhance or repress the two lncRNAs of interest and observe the effects.
“These fundamental questions are so critical for deeply understanding molecular mechanisms in the regulation of CYP-mediated drug metabolism and drug-induced liver injury,” Zhong says. “Our recent progress has placed us into an appropriate position to provide answers to these fundamental questions.”
This work will help identify novel factors that can help scientists and clinicians predict the therapeutic efficacy of a drug and risk of drug-induced liver injury.
Zhong holds a Ph.D. in molecular biology and genetics from Wageningen University. He completed postdoctoral training at Yale University. His research interests include pharmacogenetics, pharmacoepigenetics, and personalized medicine, developmental pharmacology, and epigenetic regulation of cytochrome P450s.
This work is supported by NIH Award No.: 1R35GM140862-01