Highlights
Abcam continued it’s trend of putting together unique and cutting edge events with the Crossing Boundaries: Linking Metabolism to Epigenetics meeting. Our friend, and Mass General & Harvard Med School postdoc, Stuti Mehta was on hand to cover the latest metabolism and epigenetics research in the following report:
Meeting Summary
‘Crossing Boundaries: Linking Metabolism to Epigenetics’ was the first of its kind of conference of researchers studying questions at the crossroads of Metabolism and Epigenetics. Held at the illustrious American Academy of the Art and Sciences in Cambridge, Massachusetts, the conference spanned over two days that also witnessed the arrival of summer in Cambridge. Over scrumptious food and among the witty acceptance letters of eminent fellows of the academy on display, much conversation ensued over emerging research linking epigenetics and metabolism.
The two days presented an eclectic mix of talks spanning how metabolic and epigenetic processes interact to modulate a variety of outcomes such as growth, the cell cycle and oncogenesis, the circadian clock and reprogramming and pluripotency.
Some broad themes running through the conference were:
- Availability of the methyl donor SAM and its effect on methylation of histones
- Levels of histone acetylation and their relation to the availability of Acetyl-CoA and its metabolic precursor glucose
- Mutations in the citrate metabolism enzymes IDH1 and IDH2 and how they influence the epigenome in cancer cells
- MicroRNA Let-7 as a metabolic regulator in development and cancer cell reprogramming
- Effect of metabolites such as Butyrate produced by action of certain gut microbiota on cancer cell
Histone Acetylation Modulates Intracellular pH
Siavash Kurdistani, UCLA
Dr. Kurdistani gave an engaging presentation describing a novel, non-DNA role for chromatin: regulation of intracellular pH by Histone deacetylation-dependent, and proton-coupled secretion of Acetate ions, thus impeding the increase in intracellular pH.
Global chromatin changes are a hallmark of cancer and global levels of histone modification are a prognostic indicator of clinical outcome in several cancers. Oncogenic tissues (and non-native cells that infiltrate this tissue) show a global reduction in Histone Acetylation (HAc).
Dr Kurdistani’s group observed a pH dependent reduction in HAc. Such reduction in global histone acetylation was quick, reversible on increasing the extracellular pH and affected multiple Lysine residues on both H3 and H4. Moreover, such reduction in HAc was not attributable to reduction in concentration of available Acetyl-CoA, since the levels of Acetyl-CoA remained constant at decreasing pH.
Using radiolabelled 3H-acetate, the researchers went on to show that a reduction of extracellular pH results in increased secretion of the Acetate anion in an H+-coupled, monocarboxylate Transporter (MCT)-dependent manner, thus resisting a drop in intracellular pH. Treatment with HDAC inhibitors resulted in decreased acetate secretion from cells, confirming that the Histone Deacetylation was the source of the Acetate ions secreted when extracellular pH was reduced. Conversely, global histone acetylation levels increase in response to an increase in pH.
Thus, when extracellular pH changes, regulation of intracellular pH is achieved at least in part, by export or import of Proton-coupled Acetate. The dynamic process of Histone acetylation and deacetylation functions as a sink or source of the acetate anions respectively. Chromatin was presented as a ‘rheostat’ for intracellular pH.
The Epigenetic Language of the Circadian Clock
Paolo Sassone-Corsi, University of California, Irvine
Dr. Sassone-Corsi talked about the effect of a high fat diet on the metabolome and the transcriptome, and how some of these effects are epigenetically mediated. Disruption of circadian rhythms is known to lead to metabolic diseases. Conversely, circadian rhythms are highly susceptive to changes in diet. Thus, circadian clocks are inherently connected to metabolic processes, and the concentration of about 50% of known metabolites oscillate.
Mice were fed either high fat diet (HFD) or normal caloric diet (ND) for 10 weeks. Over 24 hr liver tissue was collected at 4 hr intervals and the transcriptome and metabolome analysed by MS. Not only did a HFD disrupt normal oscillations of metabolites and transcripts, it also induced normally non-oscillating metabolites and transcripts to oscillate.
While the transcript levels and protein phosphorylation profiles of two circadian genes CLOCK and BMAL hadn’t changed in mice on HFD compared to mice on ND, the pattern of (circadian) recruitment of the CLOCK-BMAL complex to chromatin changed in mice on a HFD. Metabolites NAD+, Uridine and Uracil, that are known to be CLOCK-BMAL regulated, lost their rhythmicity in mice on a HFD. Moreover, the oscillation of H3K4me3, a robust epigenetic marker of circadian transcription was reduced at promoters of Nampt and Upp2 in HFD mice. Nampt is part of the machinery that aids oscillation of NAD+. Upp2 is a Uridine phosphorylase.
PPARγ, coding for a nuclear receptor involved in glucose and lipid metabolism was one of the genes that showed induced oscillation on a HFD. Dr. Sassone-Corsi proposed that such a gain of oscillatory expression in PPARγ provides an evolutionary benefit by inducing adipogenesis during sporadic access to a HFD in unpredictable nutrient availability environments.
Metabolic Reprogramming Regulates Tumor Cell Histone Acetylation
Kathryn Wellen, University of Pennsylvania
Dr. Wellen presented their work demonstrating that levels of tumor cell histone acetylation depends on availability of Acetyl-CoA, the availability being mediated by oncogenic metabolic reprogramming.
Dr. Wellen’s data showed that glucose availability determines Acetyl-CoA and Histone Acetylation levels in cancer cells. Moreover, that the nuclear ratio of acetyl-CoA to coenzyme-A modulates the global levels of histone acetylation.
In a doxycycline-inducible Akt deletion, the researchers observed an increase in global HAc levels within 96 hours post induction. In vitro analyses showed that a global reduction in HAc was rescued by Acetyl-CoA. Also, an overexpression of Akt resists reduction in HAc. Furthermore, Akt modulates HAc by influencing Acetyl Co-A production in two ways: by influencing glucose uptake by cells, and by inducing phosphorylation/activation of ATP-citrate lyase.
Dr. Wellen also observed that an increase in HAc is highly correlated to an increase in pAKT in samples of human glioma and prostrate cancer.
**EpiGenie gives our thanks and appreciation to Stuti Mehta, who is a Postdoc at Mass General, and Harvard Medical School, for supplying us with this conference coverage**