As our lifestyles become increasingly demanding, we build our lives around artificially divided days and nights that accommodate the need to work night shifts, stay up all night, or travel between continents. But this impacts our natural body clocks, with unwanted consequences. If we tamper with our circadian rhythms – set by the body clocks that regulate all the automated processes that take place inside the body – we tamper with our health. Our body clocks control metabolism, contributing to the proper functioning of every organ in our bodies. However, if we regularly bypass our natural day to night cycles – by working through the night, traveling long-distance, or spending too much time looking at bright screens in the dark – our body clocks become disoriented and stop functioning correctly. New research from the University of Southern California in Los Angeles, The Scripps Research Institute in La Jolla, CA, and Nagoya University in Japan identifies a key mechanism that links the dysregulation of circadian rhythms with a greater exposure to chronic diseases. “Epidemiological studies are consistently revealing more and more connections between modern lifestyles and our internal biological clock, and when those two clash, it can lead to development of diseases such as obesity and breast cancer,” notes study author Steve Kay, Provost Professor of Neurology, Biomedical Engineering and Biological Sciences at the University of Southern California. However, he adds, “This study goes beyond the epidemiology to explore the mechanisms of circadian disruption as a risk factor for certain diseases.” The new study, which appears in PNAS, has identified a protein that plays a dual role in the context of the circadian rhythm, and which explains how disrupted body clocks can lead to disease. Kay and colleagues focused on HNF4A, a protein found in cell nuclei, which previous research suggested is involved in the early development of the liver, kidney, and large intestine. When the researchers analyzed liver and colon cells taken from mouse and human tissue, they found that HNF4A interacts with the circadian clocks of these cells in complex ways. More specifically, HNF4A can block two other proteins – CLOCK and BMAL1 – that help regulate circadian rhythms in mammals. “Inside the cell, the cogs of the clock are universal, but the hands of the clock are specific to each organ, so how the clock does its work in each cell is different,” explains Kay. HNF4A, it turns out, responds to chemical signals within the cell and acts out on other proteins in accordance. This means that when this protein’s activity goes haywire, normal metabolic processes are also disrupted, leaving the organs more exposed to disease. “So, in the liver, we looked at tissue-specific proteins and found that HNF4A is tied to the circadian clock, is regulated by the clock and cycles with the clock and, in turn, regulates the clock. That’s the new finding here, and it’s a big jump forward,” said Steve Kay. As the study’s first author, Meng Qu, also explains, “Mutations in [the] HNF4A gene are known to contribute to a rare hereditary form of diabetes called MODY1, and its expression dysregulation has been closely linked to liver cancer, both with mechanisms we don’t fully understand.” “Our discovery suggests the clock disruption could be a potential mechanism and provides a bridge between circadian regulation and development of disease,” she adds. Modern lifestyles often demand that we live by irregular rhythms, and the researchers warn that this can contribute to the disruption of sensitive mechanisms, including the ones in which proteins, such as HNF4A are involved. “Humans are not evolved for night shifts, nighttime lights, and intercontinental travel. Modern-life challenges to our circadian system present a long-term threat to our health,” says Kay. Discoveries such as the one highlighted in the current study can offer us a more detailed picture of how disrupted body clocks can affect health outcomes. “Now we can see how HNF4A is a new chapter in a book that was mostly blank pages, so there’s a story beginning there as we fill in a huge blank spot,” Kay encourages. Published in Daily Times, December 15th 2018.