Revealing the crosstalk between one carbon metabolism, SAM availability and chromatin methylation - PROJECT SUMMARY Early in my career I became intrigue by the fact that chromatin modifications included chemical modifications that were dependent on metabolites, yet very little was known on how cells connected metabolic input to chromatin reactions. Work in my lab identified SIRT6 as a critical chromatin deacetylase, repressing glycolytic and ribosomal genes to control metabolic homeostasis. We also found SIRT6 as a major tumor suppressor in multiple cancers, inhibiting glycolysis (Warburg effect) and developmental genes. Through all this work, I pioneered the concept that metabolism and epigenetics crosstalk in cells, a field now explored by hundreds of laboratories. Through the years, we also explored roles for chromatin in DNA repair and development, including the first human syndrome of SIRT6 deficiency; we discovered SIRT6 as a driver of transcriptional pausing, and more recently discovered that metabolic adaptations in cancer occur only in tumor propagating cells, thus defining metabolism as yet another feature of cancer heterogeneity. Overall, my laboratory has provided innovative insights that changed the way we think about metabolism and chromatin dynamics. Work from us and others defined that availability of Acetyl-CoA is regulated in sub-cellular compartments, in order to secure a sufficient source in the nucleus for histone acetylation reactions. Notably, and in contrast to acetylation, despite methylation reactions being the most abundant modification in DNA and histones, how levels of the universal methyl donor S-Adenosyl-methionine (SAM) is regulated remains completely unknown. Strikingly, we have found in preliminary work that the enzymes modulating SAM appear to shuffle between different cellular compartments depending on nutrient conditions, an adaptation that appears to be critical both in normal and transformed cells. In the past decade of work, we contributed significantly to the understanding of acetyl-modifications in chromatin and its connection the cellular metabolism. In the next few years, we will take advantage of novel metabolic sensors and reporters, high- resolution mass spectrometry and biochemical approaches to investigate how one carbon metabolism is modulated in cells, how different cellular compartments cope with changing nutrients, and whether and how metabolic enzymes are mobilized inside cells to be part of nuclear complexes in order to provide in situ SAM for locus-specific methylation reactions. Despite SAM being a central metabolite in one carbon metabolism and the universal donor for methylation reactions, how its availability influence epigenetic modifications and vice versa, how chromatin dynamics dictate SAM metabolism, remains virtually unknown. Given the critical roles for DNA and histone methylation in every aspect of organismal biology, from early development, to cellular differentiation, cancer and ageing, our results will provide critical new insight into the molecular mechanisms connecting these chromatin modifications to nutrient availability and metabolism.
