As we all know that the human body can function adaptively as the day and night change. And according to a new research from the Perelman School of Medicine at the University of Pennsylvania, a key protein called Rev-erb coordinates the ebb and flow of Gene expression by tightening and loosening loops in chromosomes.
For the past 15 years, Mitchell A. Lazar et al. have been dedicated to revealing the molecular mechanisms by which Rev-erb proteins regulate the body’s molecular clock, metabolic homeostasis, and brain health.
“Many studies, including this present one, point to a connection between the human internal clock and such metabolic disorders as obesity and diabetes,” said Lazar. “Proteins like Rev-erb are the gears of the clock and understanding their role is of great importance for investigating these and numerous different diseases.”
The body’s Gene Expression has a significant diurnal characteristic, and this effect is controlled by the body’s molecules “clock”. Core clock proteins activate or inhibit protein complexes’ function that physically loops one part of a chromosome to become adjacent to a distant part of the same chromosome.
Previously, researchers have found that Rev-erb regulates the circadian expression of genes in the liver of mice, a function that is based on its interaction with chromosomes. Previous studies have found that by 5 p.m., Rev-erb increases to its highest level in mouse liver, while it steadily decreases and nearly vanishes from the liver by 5 a.m. as the day turns to night.
Without Rev-erb regulation, downstream target genes are able to restore their expression, so the circadian expression of Rev-erb-regulated genes is repeated day in and day out under normal conditions. It has been previously found that the activation of the protein can promote the formation of the circular region of the chromosome to activate gene expression. However, how Rev-erb down-regulates gene expression still remains unclear.
In this study, the researchers found that Rev-erb protein can inhibit gene transcription by relaxing the circular region of the chromosome, and Rev-erb kicks out the protein complexes that bridge the distant regions of the chromosome, thereby destabilizing the loop and turning off the gene.
The team intends to look at new drugs that affect chromosome looping to see how it may affect gene expression in cancer cells and tissues other than the liver.
Reference
Yong Hoon Kim, Sajid A. Marhon, Yuxiang Zhang, David J. Steger, Kyoung-Jae Won, Mitchell A. Lazar. Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription. Science, 2018; eaao6891 DOI: 10.1126/science.aao6891
