Clinical OMICS

MAY-JUN 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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In the Lab 38 Clinical OMICs May/June 2018 www.clinicalomics.com New evidence from investigators at the University of Tokyo and Tohoku University in Japan has revealed a molecular mechanism that controls how lifestyle choices and the exter- nal environment affect gene expression. This mechanism includes potential targets for next-generation drug discov- ery efforts to treat metabolic diseases including diabetes and obesity. The Japanese researchers tracked how the epigenome changes after long-term exposure to cold temperatures, and how those changes cause energy-storing white fat cells to become heat-producing brown-like, or "beige," fat cells. Findings from the new study were published in Nature Com- munications through an article entitled "Histone demethy- lase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch." "We believe that this is the first time that anyone has col- lected data to prove that there are two steps between the environmental stimuli and epigenetic changes," explained Juro Sakai, M.D., Ph.D., an expert in the epigenetics of metabolism and professor at the University of Tokyo and Tohoku University. Shivering creates body heat short-term by warming up the muscles, but thermogenesis is the chemical process by which brown fat cells can use lipids (fat) to create heat to keep the body warm long-term. Brown fat is regarded as healthier and is not associated with the metabolic diseases linked to excess white fat. Scientists have long suspected that there may be a stepwise process inside the cell to man- age environmental influences on the epigenome, but no spe- cific molecular mechanisms had been identified previously. "Understanding how the environment influences metabo- lism is scientifically, pharmacologically, and medically inter- esting," Sakai noted. Researchers have shown previously that when organisms are cold for a long time, the sympathetic nervous system responds by releasing adrenaline. If cold temperatures per- sist, those adrenaline signals eventually reach white fat cells. In the current study, the research team set out to uncover the epigenetic control pathway that the cell initiates to make the necessary metabolic switch. The investigators showed the switch "occurs through a two-step process that requires both β-adrenergic-dependent phosphorylation of S265 and demethylation of H3K9me2 by JMJD1A. The histone demethylation-independent acute Ucp1 induction in BAT and demethylation-dependent chronic Ucp1 expression in beige scWAT provides comple- mentary molecular mechanisms to ensure an ordered tran- sition between acute and chronic adaptation to cold stress. JMJD1A mediates two major signaling pathways, namely, β-adrenergic receptor and peroxisome proliferator-acti- vated receptor-γ (PPARγ) activation, via PRDM16-PPARγ- P-JMJD1A complex for beige adipogenesis." In short, the epigenetic changes transform white fat cells into beige fat cells, which perform thermogenesis like brown fat cells. More beige fat cells and fewer white fat cells could reduce the symptoms or negative health outcomes of metabolic diseases like diabetes, obesity. Although trans- forming white fat cells into beige fat cells and increasing thermogenesis is naturally a stress response to chronic cold exposure involving adrenaline, researchers report that the same white-to-beige fat cell transition can be caused with- out adrenaline or cold stress. "Our next experiments will look more closely at epigen- etic modifications within the thermogenesis signaling path- way so that we may manipulate it," said Sakai. Exposure to Cold Spurs Epigenetic Changes in Fat Cells Ugreen / Getty Images

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