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Study Links Epigenetic Enzyme to Mouse Liver Circadian Rhythms

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A study appearing online today in Science is offering insights into the epigenetic underpinnings of the daily cycles of fat production observed in the liver.

Researchers from the University of Pennsylvania and the Dana-Farber Cancer Institute used a combination of chromatin immunoprecipitation and massively parallel sequencing to characterize associations between genomic DNA and histone deacetylase 3 — an enzyme that curtails the acetylation of histone proteins — in the livers of mice kept on specific light-dark cycles and feeding regimens.

Their results suggest that HDAC3 interactions with genomic DNA vary with the liver's circadian cycle, plummeting at night when mice are active and eating and peaking during the day when the animals are dormant. When it is recruited to genomic DNA, the team found, the enzyme often turns up near lipid metabolism genes, apparently keeping these genes less active at times of the day when mice sleep — regulation that seems to stave off a condition known as fatty liver.

"This work shows that the epigenome, which is critical for regulating how genes are expressed, undergoes reversible remodeling every day," senior author Mitchell Lazar, a genetics researcher at the University of Pennsylvania, said in a statement. "This leads to a circadian rhythm of metabolism that is important, because disruption of this rhythm leads to fatty liver."

Fat production in the liver varies over the span of a day and appears to be influenced by light, sleep, and food consumption patterns, researchers explained. It's unclear what molecular processes control these cycles, they added, though past studies have shown that gene expression and epigenetic patterns sometimes oscillate over time in other organs with metabolic functions.

To explore the possibility that similar processes govern the liver's circadian rhythms, the team decided to look at time-dependent interactions between HDAC3 and genomic DNA in the mouse liver in ChIP-seq experiments using HDAC3-specific antibodies.

Although HDAC3 is one of several proteins influencing epigenetic processes in the liver, they explained, the enzyme's previously reported ties to both circadian rhythm and glucose-related processes piqued the team's interest.

Indeed, the researchers found that the number of interactions between HDAC3 and DNA varied with time. During the light period when mice usually sleep, HDAC3 was associated with more than 14,000 sites in the mouse liver genome. On the other hand, it was detected at just 120 sites in the genome during the dark period when mice are active and eating.

This pattern persisted even when the mice were kept in the dark all day, they noted, indicating that it was an authentic circadian cycle.

Nevertheless, they found that they could flip the timing of HDAC3-DNA associations in the cycle by giving mice food only during the light period when they're normally inactive.

Based on these and other experiments, the team speculated that the HDAC3 enzyme is recruited to the liver genome during inactive periods of the day to regulate fat producing genes — associations that seem to rely on a nuclear receptor protein known as Rev-erb-alpha.

When they do make their way to the genome, both HDAC3 and Rev-erb-alpha tend to turn up around lipid metabolism genes, the researchers reported, apparently lowering the expression of these genes.

Moreover, they reported, mice missing either the HDAC3 enzyme or the Rev-erb-alpha receptor accumulate excess fat in their livers, underscoring the importance of the histone acetylation circadian rhythm in liver function.

Researchers say the results so far "demonstrate the existence of circadian changes in histone acetylation whose dysregulation has the potential to cause major perturbations in normal metabolic function."

Moreover, they suspect similar epigenetic mechanisms may be at play in human livers as well. If so, they argue, it's possible that some of the previously reported ties between unusual sleep patterns and the risk of obesity and related diseases may stem from interruptions to these sorts of epigenetic cycles.

"Misalignment of fasting/feeding and sleep/wake cycles could disrupt the rhythm of HDAC3 association with target genes and contribute to the fatty liver observed in rotating shift workers as well as people with genetic variants of molecular clock genes," the researchers concluded.

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