Postnatal excision of HDAC3 from the heart and skeletal muscle of mice caused severe hypertrophic cardiomyopathy and heart failure when fed a high-fat diet.
Researchers from the University of Pennsylvania Perelman School of Medicine (PA, USA) have discovered that the epigenetic modifier histone deacetylase 3 (HDAC3) could act as a molecular link between high-dietary fat intake and heart failure.
“We have shown that HDAC3 regulates cardiac metabolism, gene expression and function in a manner that is strongly influenced by diet,” Mitchell Lazar, Director of the Institute for Diabetes, Obesity and Metabolism at the Perelman School of Medicine, explained to Epigenomics. “The lethality of the high-fat diet in mice lacking HDAC3 dramatically demonstrates the critical function of the epigenome is responsible for the interaction between gene expression and the environment,” he continued.
The Lazar laboratory at the University of Pennsylvania School of Medicine explores the effects of epigenomic regulation on metabolism and how these are influenced by environmental factors – such as nutrition, daily rhythms, hormones and drugs interacting with nuclear receptor pathways.
Embryonic, cardiac-specific deletion of HDAC3 in mice has recently been performed by researchers at the University of Texas Southwestern Medical Center (TX, USA) and the Oklahoma Medical Research Foundation (OK, USA). This was shown to cause major cardiomyopathy in mice with survival rates not exceeding 4 months, independent of diet.
However, in this current study from the Lazar laboratory, published online ahead of print in the Journal of Biological Chemistry, the researchers found that deletion of myocardial HDAC3 did not impair survival in mice fed on chow with a normal fat content, although there were signs of fat accumulation in the cardiac tissue.
“We were initially puzzled by the difference in our findings, then realized that in our model HDAC3 was deleted after birth, while the other model involved deletion in early embryogenesis. This underscores the role of timing as well as environment in the maintenance and function of the epigenome,” Lazar explained to Epigenomics.
Upon switching to a high-fat diet, the mice lacking HDAC3 began to die within weeks, displaying signs of severe cardiomyopathy and heart failure. Comparison of gene-expression patterns in the HDAC3-negative mice and those still expressing the gene revealed that those with the deletion were underexpressing genes associated with lipid metabolism and energy production. This suggests that deletion of the epigenetic modifier HDAC3 impairs the ability of the cardiac mitochondria to respond to the increased fat intake. “These findings support the increasing realization that the epigenome is responsible for the interaction between gene expression and the environment; in this case, the nutritional environment,” elaborated Lazar.
In addition to the above findings, the study demonstrated a mouse model for diet-inducible heart failure.
Lazar went on to explain to Epigenomics as to how the group intended to further their research: “We will be studying the genomic targets of HDAC3 in the heart and comparing them with the genomic targets in other tissues such as the liver, which we have already published. We will also test various therapies and their ability to ameliorate the deleterious effects of diet on mice lacking cardiac HDAC3. We would like to trace the components of the high-fat diet that are responsible for its deleterious effects in the absence of HDAC3, which will require in vivo tracers and flux studies of metabolism.”
– By Sarah Miller
Sources: Sun Z, Singh N, Mullican SE et al. Diet-induced lethality due to loss of HDAC3 in heart and skeletal muscle. J. Biol. Chem. 286(38), 33301–33309 (2011); Montgomery RL, Potthoff MJ, Haberland M et al. Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. Clin. Invest. 118(11), 3588–3597 (2011); Feng D, Liu T, Sun Z et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331(6022), 1315–1319 (2011).
Scientists at the Johns Hopkins University School of Medicine (MD, USA) have produced new evidence to suggest that DNA methylation in nonmitotic cells may not be as stable as previously believed. A comparison of CpG methylation in adult mouse neurons before and after in in vivo electrical brain stimulation revealed widespread, active changes in methylation status following neuronal activity. The paper was published in the October 2011 issue of Nature Neuroscience.
“Our study shows active DNA modification in neurons is extensive and also reveals a number of global properties of this regulation. These data sets are also the foundation to further understand epigenetic regulations in the nervous system in the future,” explained Hongjun Song, Professor of Neurology and Neuroscience at the Johns Hopkins University School of Medicine and a corresponding author of the study, when speaking to Epigenomics.
“This work is important because it comprehensively characterized neuronal activity-dependent DNA modification dynamics in the nervous system in vivo. Previously, many works have identified a number of dynamic loci in the genome, but the spectrum of this regulatory mechanism across the genome was unknown,” continued Song.
The study used methylation-sensitive cut counting to determine the methylation profiles in nondividing mouse dentate granule neurons prior to and following in vivo electrical stimulation. “This method is based on methylation-sensitive restriction enzyme HpaII and its insensitive isoschizomer MspI,” Song explained to Epigenomics.
Using this method, methylation was studied in a total of 219,991 CpG dinucleotides. 1.4% of CpGs were found to undergo rapid, active demethylation or de novo methylation in response to stimulation, with significant changes occurring in low-CpG density regions. Some of these modifications were stable for up to 24 h. Affected dinucleotides had a broad genomic distribution and were associated with brain-specific genes implicated in neuronal plasticity.
In addition to challenging the previously held belief that DNA methylation in the brain is relatively stable, these discoveries also have wider implications. Song elaborated: “The method we used to synchronously activate dentate granule neurons, electroconvulsive stimulation, is analogous to a therapy currently used to treat clinical depression patients. However, the underlying mechanism of this therapy is still debated. Regulation of DNA methylation might underlie its mode of action. Our study also suggests that epigenetic regulations might be potential targets for neurological and psychiatric diseases.”
– By Sarah Miller
Source: Guo JU, Ma DK, Mo H et al. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat. Neurosci. 14, 1345–1352 (2011).
Detailed mapping of previously described miRNAs located on mouse and human X chromosomes has recently been carried out by researchers at the Flanders Institute for Biotechnology (Ghent, Belgium) and Ghent University (Ghent, Belgium), prompting the hypothesis that X-chromosome-located miRNAs may be responsible for the immunological advantage observed in females compared with males. The paper is published in the November 2011 issue of the journal BioEssays, and the authors suggest that the X-linked miRNAs could also play a role in reduced cancer susceptibility observed in females.
“Statistics show that in humans, as with other mammals, females live longer than males and are more able to fight off shock episodes from sepsis, infection or trauma,” explained Claude Libert, group leader at the Flanders Institute for Biotechnology. In addition, females are also less likely to develop cancers.
The observed immunological advantage for females has been attributed to genetic imprinting, which is an X-chromosome-associated mechanism. The new research proposes that this could also influence miRNAs, in addition to genes. Libert elaborates: “We believe the immunological advantage in females is due to the X chromosome, which in humans contains 10% of all miRNAs detected so far in the genome. The roles of many remain unknown, but several X-chromosome-located strands of miRNA have important functions in immunity and cancer.”
“Gene silencing and inactivation skewing are known mechanisms which affect X-linked genes and may influence X-linked miRNAs in the same way,” continues Libert. To develop this hypothesis, the group produced a detailed map of all the currently described X-linked miRNAs, highlighting those associated with immune functions and oncogenesis.
This theory highlights the potential significance of epigenetic regulation in the observed differences between male and female immunity and oncogenesis. Summarizing his group‘s findings, Libert concluded: “How this unique form of genetic inheritance influences X-chromosome-linked miRNAs will be a challenge for researchers for years to come, not only from an evolutionary point of view, but also for scientists investigating the causes and cures of disease.”
– By Sarah Miller
Source: Pinheiro I, Dejager L, Libert C. X-chromosome-located microRNAs in immunity: might they explain male/female differences? BioEssays 33(11), 791–802 (2011).
Recent research from King‘s College London Institute of Psychiatry (London, UK) has provided fresh insight into the significance of DNA methylation in the development of the major psychoses schizophrenia (SZ) and bipolar disorder (BD). The study, published online in September 2011 in the journal Human Molecular Genetics, was the first to compare genome-wide DNA methylation in sets of monozygotic (MZ) twins discordant for SZ and BD. The findings confirmed the importance of epigenetic alterations in the etiology of SZ and BD, and potentially offer novel therapeutic targets for future antipsychotic development.
In the study, multiple loci demonstrated psychosis-associated DNA methylation differences, with a region in the ST6GALNAC1 promoter demonstrating the most significant methylation differences between affected and unaffected individuals. This locus overlaps with a previously reported genetic abnormality associated with SZ. Analysis of DNA methylation in postmortem brain tissue from psychosis patients confirmed that this region exhibits significant hypomethylation in some affected individuals.
Studies have estimated heritability for SZ and BD to be approxiamtely 70%; however, MZ twin pairs exhibit disease concordance that is far from 100%, suggesting that nongenetic factors must play a significant role in disease etiology. “We studied a group of 22 identical twin pairs, so 44 individuals in all; one of the largest twin studies performed for any complex disease to date. In each twin pair, one had either SZ or BD disorder. Because we know that twins are genetically identical, we can rule out any genetic cause of illness in the affected twin – the aim of our study was to investigate epigenetic variations associated with these disorders,” explains Jonathan Mill, lead author of the study.
In this study, genome-wide analysis of DNA methylation on peripheral blood DNA samples from the MZ twin pairs was performed. This revealed disease-associated DNA methylation differences at numerous loci, not only between twins discordant for SZ and BD individually, but also as a combined major psychosis group. Mill et al. found that these epigenetic differences occurred at regions known to be directly associated with neurodevelopment and psychosis.
The most significant hypomethylation was found in the promoter region of ST6GALNAC1, which exhibited a mean DNA methylation difference of 6%; however, differences at this locus were highly heterogenous and found to be up to 20% in some twin pairs. Consequently, the King‘s College group studied DNA methylation in this region in an independent sample of postmortem brain tissue from psychosis patients and a control sample, discovering a hypomethylation value of over 25% in a subset of affected patients.
Mill summarizes: “Our findings suggest that it is not only genetic variations that are important. The epigenetic differences we see may tell us more about the causes or SZ and BD, as some alterations were specific to either disease. Importantly, epigenetic processes are potentially reversible meaning that our research could open up new avenues for the development of novel therapeutic drugs.”
– By Sarah Miller
Source: Dempster EL, Pidsley R, Schalkwyk LC et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum. Mol. Genet. doi:10.1093/hmg/ddr416 (2011) (Epub ahead of print).