Crossing boundaries: linking metabolism to epigenetics (report - day 2)

Meeting report on day 2 of Crossing boundaries: linking metabolism to epigenetics, Cambridge, MA, 1-2 May 2014.

By Heather Allan

Abcam Scientific Support Specialist, Boston.

The first session of day two focused on signaling in metabolism and epigenetics. The regulation of cellular physiology by histone acetylation was discussed in the context of cancer initiation and progression.

Siavash Kurdastan demonstrated that histone acetylation and deacetylation work to regulate intracellular pH.

This emphasize the unanticipated link between histone modifications and methbolism where chromatin functions as a rheostate for intracellular pH regulation, by regulating the flux of acetate. A process that has important implications for cancer therapeutics.

Paolo Sasson-Corsi presented his work on epigenetic and circadian rhythm.

The circadian clock machinery incorporates mRNA expression, protein stability, global chromatin states, and metabolite abundance to track time. Metabolites and levels of Acetyl CoA oscillate within this time.

The reprogramming of the clock is nutrition driven and reversible, which is very important from an evolutionary perspective.

Lysine acetyltransferases CBP and p300 although very homologous and able to acetylate all four core histones, have distinct specificity towards different lysine residues.

Andrew Andrews discussed how his lab has been able to use a label free quantitative mass spectrometry assay to unravel the specific lysine residues for each acetyltransferase.

The search for small molecules that can alter selectivity of these two enzymes provides new possibilities for targeted therapeutics.

Brandon Nicolay drew our attention to the classic p16/RB tumor suppressor pathway.  Metabolic and flux studies in Drosophila and human cells indicate that loss of pRB sensitizes cells to oxidative stress through a decrease in the Glutathione pool.

Interestingly, the proliferative rate of pRB deficient cells is sensitive to aminotransferase inhibition under oxidative stress conditions.

John Whetstine presented data that links histone lysine demethylase KDM4A/JMJD2A to localized copy number changes without affecting global chromosomal instability.

The level of KDM4A is regulated throughout the cell cycle by the SCF E3 ubiquitin ligase complex. The site specific copy gains can be induced by KDM4A over expression and may have a role in tumorigenesis and chemotherapy resistance.

Metabolic regulation of stem cell  pluripotency was discussed by George Daley. The Daley lab have shown that human ESCs (hESCs) require glucose and glycine for SAM biogenesis and eventual histone methylation.

Over expression of metabolic enzymes such as threonine dehydrogenase (Tdh) enhance reprogramming of human fibroblasts into  iPSCs indicating the involvement of Thr-Gly-SAM flux in epigenetic reprogramming.

In addition, the role of LIN28, an RNA binding protein, was discussed in glycolytic metabolism of pluripotent stem cells.

The last session of the conference was focused on exploring the link between metabolism and chromatin dynamics in organismal models.

The role of  SIRT1 in tissue maintenance and aging was presented by Leonard  Guarente, using a KO mouse model which show aberrant stem cell changes during calorie restriction (CR).

CR mediated responses in the gut cells are differentially regulated by mTOR in Paneth cell and SIRT1 in stem cells.

The work of Scott Bultman shows us how the microbial metabolite Butyrate links dietary fiber to its potent tumor suppressive effects.

The Warburg effect in tumor cells will stimulate butyrate accumulation. This amplifies HDAC inhibition and induction of apoptosis in tumor cells.

Dietary fiber in combination with butyrate producing bacteria can induce endogenous HDAC inhibitors that can account for a probiotic/prebiotic chemoprevention strategy.

Ruri Kaneda’s lab showed that H3K9me3 levels on repetitive loci, pericentromeric and telomeric regions, are significantly altered in failing heart.

They have identified a subset of these silenced loci to be repetitive elements neighboring mitochondrial genes.

Excessive silencing of these regions contributes to chronic heart failure. Cheatocin, a H3K9 histone methyltransferase inhibitor delayed the transition from cardiac hypertrophy to heart failure in animal models.

The closing presentation by Bess Frost drew our attention to tauopathy and neurodegenerative disease.

Oxidative stress-induced DNA damage causes widespread loss of heterochromatin. This leads to cell death in tauopathy induced in the brains of human tau transgenic Drosophila and mice.

Tau-induced transcriptional activation leads to increased expression of Ago3, which seems to play a key role in neurodegeneration. This study also finds a large scale transcriptional increase in human Alzheimer’s disease (AD) brains and reveals potential therapeutic targets for AD.

If you want to read more about Crossing Boundaries: Linking Metabolism to  Epigenetics, take a look at day 1 of the conference.