Clock Protein Controls Daily Cycle of Gene Expression by Regulating Chromosome Loops


Source: University of Pennsylvania

Summary: According to new research, the up-and-down daily cycles of a long-studied clock protein called Rev-erb coordinates the ebb and flow of gene expression by tightening and loosening loops in chromosomes.


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. Over the last 15-plus years, a research team from the University of Pennsylvania 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. They found that the up-and-down daily cycles of this long-studied clock protein called Rev-erb coordinates the ebb and flow of gene expression by tightening and loosening loops in chromosomes. The research findings were published in the journal Science.

Clock Protein

Schematic of Rev-erb’s role in gene expression. At night (left), when Rev-erb concentration decreases, gene expression is turned on by protein complexes that loop the chromosome bringing together distant regions (blue and pink). During the day (right), when Rev-erb levels rise, the protein complexes are kicked out, causing the loop to loosen and turn off gene expression. Credit: Yong Kim and Mitch Lazar, Perelman School of Medicine, University of Pennsylvania

The 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. Rev-erb kicks out the protein complexes that bridge the distant regions of the chromosome, thereby destabilizing the loop and turning off the gene. Without Rev-erb around, expression of its target genes returns. This study points a link between the human internal clock and metabolic disorders as obesity and diabetes.

Senior author Mitchell A. Lazar said, “The mechanisms by which Rev-erb loosens loops in DNA, leading to circadian repression of transcription, are likely to apply to other clock proteins.”


More Information: Yong Hoon Kim et al. Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription, Science (2018).DOI: 10.1126/science.aao6891, science.sciencemag.org/content … 2/07/science.aao6891


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