Crossing boundaries: linking metabolism to epigenetics (report - day 1)

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

By Panthea Taghavi

Abcam Scientific Support Specialist, Boston.

This meeting brought together experts in the emerging and growing branch of epigenetics, which links metabolic homeostasis to transcriptional regulation and genomic integrity.

On day one, the molecular mechanism underlying glucose metabolism by SIRT6 was discussed by Raul Mostoslavsky.

SIRT6 acts as a tumor suppressor co-repressing Hif1alpha and inhibiting the Warburg effect. In addition, SIRT6 plays a role in genomic stability through recruiting chromatin remodelers to sites of DNA breaks.

Eric Verdin highlighted further how SIRT3 and SIRT5 regulate multiple metabolic pathways through the selective regulation of lysine acetylation and succinylation of mitochondrial proteins.

An elegant model for biliary cancer was discussed by Nabeel Bardeesy where isocitrate dehydrogenase IDH mutations cause 2-hydroxyglutarate (2HG) accumulation, which results in epigenetic reprogramming and tumorigenesis.

Furthermore, Ari Melnick discussed how IDH1 and  IDH2 mutations in acute myeloid leukemia (AML) lead to a specific DNA hypermethylation signature through inhibition of Tet Methylcytosine Dioxygenase 2 (TET2).

Methionine cycle metabolism and S-adenosylmethionine (SAM) availability were the focus of presentations by Jason Locasale and Stacey Borrego. Methionine availability and one carbon metabolism are dynamically affected by diet and these in turn regulate global histone methylation changes through SAM abundance.

Stacey showed that cancer cells are different from normal cells in their methionine dependence.

Methionine stress leads to SAM limitation and cell cycle arrest in cancer cells through destabilization of pre-replication complexes. This identifies the methionine metabolism pathway as an interesting target for therapy.

Benjamin Tu highlighted the role of Acetyl-CoA in cell growth and transformation. He discussed how metabolic and nutritional cues affect cell cycle and lifespan in yeast through chromatin remodeling.

Kathryn Wellen’s lab is unraveling signaling pathways that link nutrient uptake and metabolism to alterations is gene expression patterns and cell transformation.

A striking example is when  oncogenic activation of AKT is followed by transcriptional profile changes through acetyl-CoA induction and histone acetylation. This indicates an important role for Acetyl-CoA metabolism in tumor development and progression.

Maria Soloveychik presented a fascinating link between  histone demethylation and mitochondrial respiration levels in yeast through alpha-ketoglutarate (alphaKG).

Elevated  alphaKG by tricarboxylic acid cycle flux leads to demethylation of H3K4me3 by Jumonji-family proteins. This transcriptional remodeling results in repression of electron transport genes and limits replicative life span.

The biological relevance of histone ADP-ribosylation as a novel member of histone code post-translational modifications was discussed by Michael Hottiger. NAD+ dependent ADP-ribosyltransferase PARP1 is shown to ADP-ribosylate lysine and glutamate residues of histones.

These residues are also subject to acetylation and methylation which confirms the crosstalk between histone modifications.

Blerta Xhemalce discussed the intriguing world of post-translational modifications of noncoding RNAs.

Noncoding RNAs are becoming progressively more important players in regulation of gene expression. BCDIN3D has been identified as a RNA methyltransferase and has been linked to obesity and type II diabetes linking RNA modifications to metabolism.

Day one of this lively meeting ended with an exciting poster session extending the discussions on various aspects of epigenetic plasticity influenced by metabolism.

If you want to read more about Crossing Boundaries: Linking Metabolism to Epigenetics, take a look at Day 2 of the conference.

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