Over the last 15-plus years, a team led by the new study’s senior author Mitchell A. Lazar, MD, PhD, director of Penn’s Institute for Diabetes, Obesity, and Metabolism, has been teasing out the versatile role of Rev-erb in maintaining daily cycles of the body’s molecular clock, metabolism, and even brain health.
“Many studies, including this one, point to a link between the human internal clock and such metabolic disorders as obesity and diabetes,” Lazar said. “Proteins such as Rev-erb are the gears of the clock and understanding their role is important for investigating these and many other diseases.”
Human physiology works on a 24-hour cycle of gene expression (when the chromosome coding region is translated by RNA and then transcribed to make protein) and is controlled by the body’s molecular clock. Core clock proteins activate or repress protein complexes that physically loop one part of a chromosome to become adjacent to a distant part of the same chromosome.
The Penn team showed that daily oscillations of Rev-erb control gene expression in the mouse liver via interactions between on-and-off regions on the same chromosome. Previous work from the team demonstrated that by 5 p.m., Rev-erb increases to its highest concentration in mouse liver, where it turns off certain genes and therefore protein transcription. But as the day turns to night, its concentration steadily decreases and nearly vanishes from the liver by 5 a.m.
Without Rev-erb around, expression of its target genes returns. And this process repeats normally, day after day. Other researchers have established that activator proteins drive the formation of chromosome loops to turn on genes; however, how repressor proteins such as Rev-erb regulate their part in turning off gene expression has remained unanswered, until now.
In this study, the team demonstrated that Rev-erb represses transcription by loosening chromosome loops. 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 mechanisms by which Rev-erb loosens loops in DNA, leading to circadian repression of transcription, are likely to apply to other clock proteins," Lazar said. Recent studies have tied Rev-erb to cancer and cardiovascular disease. The team aims 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.
Other authors are Yong Hoon Kim, an MD-PhD student in the Cell and Molecular Biology Program, and Sajid Marhon, a postdoctoral fellow in the laboratory of Kyoung-Jae Won in the department of Genetics, as well as Yuxiang Zhang, David Steger, and Kyoung-Jae Won, all from Penn.
This work was supported by the National Institutes of Health (R01 DK45586, NIH R01 DK106027, NIH T32GM007170, T32 GM008216, F30 DK112507) and the JPB Foundation.
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R01 DK45586, NIH R01 DK106027, NIH T32GM007170, T32 GM008216, F30 DK112507