Schvartzman Lab at HICCC of Columbia University

Our research

Our lab seeks to understand how changes in intra- and extra-cellular metabolites affect chromatin biology. We are especially interested in how these processes play out in 1) normal physiology (for example in influencing cell fates); and 2) in cancer, in particular in colorectal cancer.

We use a combination of classic tissue culture and molecular biology techniques, patient-derived biopsies and xenografts, novel epigenetic mapping tools and bioinformatics approaches to understand metabolism and epigenetics and to discover novel treatments for cancer.

From Krebs to Weintraub, or how to go from metabolism to gene expression

Over the last two decades we have understood that DNA is not a simple linear molecule with protein-coding instructions but that the secondary and tertiary structures of DNA play a large role in which genes are turned on or off. A key player in changing whether chromatin is ‘open’ or ‘closed’ is the structure of the core component of chromatin, the nucleosome. Histone tails on nucleosome particles can be covalently modified by metabolic enzymes, ultimately leading to increased or decreased compaction between adjacent nucleosomes. Thus, histone acetyl-transferases (HATs) transfer acetyl moieties from acetyl-CoA to histone lysine residues, increasing accessibility. Conversely, histone methyl-transferases (HMTs) transfer methyl moieties from S-adenosyl methionine to histone lysine residues, most commonly decreasing accessibility. This ‘histone code’ is also dependent on ‘eraser’ enzymes, histone deacetylases (HDACs) and histone demethylases (KDMs), enzymes that use NAD and alpha-ketoglutarate and O2, respectively, to remove acetyl marks and methyl marks. This complex interplay between metabolism and chromatin carries an important prediction, that the availability of metabolic substrates dictates the chromatin landscape of a cell.

The majority of cells in our body never divide. They have instead committed to carrying out a specialized function. This specialization is dependent on a stable supply of nutrients that permit anabolic metabolism, and a stable removal of waste products that permit catabolic metabolism. Hence, as opposed to the cells of unicellular organisms, cells in metazoan organisms assume an unchanging environment and ‘double-down’ on reading a very small fraction of their genome to differentiate and carry out a very specialized function.

We have also recently began to understand that the metabolic wiring diagrams that are monolithically represented in biochemistry textbooks are much more flexible in multicellular organisms. Some cells require enormous amounts of ATP and hence rewire their metabolism to extract as much energy as possible from energy-rich nutrients (e.g. myofibers or neurons). Other cells have less of a need for ATP and a much more dire need for synthesizing the building blocks required to double their biomass (cancer cells). These cells conserve multicarbon precursors rather than burning them for energy and require NAD+ regeneration to maintain glycolysis. Yet other groups of cells require metabolic intermediates for committing to cell fate decisions. Each of these unique metabolic needs determines the availability of nutrients for chromatin-modifying reactions.

Finally, cellular homeostasis is not universal; many biological phenomena take place when blood supply is interrupted, tissue barriers break, or demand exceeds supply. These processes are at the core of pathologies like cancer, where increased demand for nutrients to facilitate proliferation clashes with impaired or altered blood supply.

  • Is differentiation responsive to different metabolic stimuli or insults?
  • Why is differentiation a generally irreversible process?
  • Can we alter the differentiation state of a cell by changing flux through metabolic pathways? Conversely, can the extra cellular environment coax a cell to de-differentiate?
  • How do pre-cancerous cells learn to ignore differentiation cues to continue dividing?
  • How do altered metabolic environments like ischemia influence these signals?
  • How do cancer cells continue to divide (a huge anabolic undertaking) despite the harsh metabolic environments present in solid tumors? Are cancer cells that develop under metabolic restrictions selectively sensitive to insults that normal cells are immune to (e.g. synthetic lethalities)?

These are some of the broad questions that my lab seeks to answer.