May 1, 2017 – Many of the genes we study at the NRI are involved in nutrient metabolism. One of the ways we can learn about what a gene does is to delete it in an animal model and then see how the gene-deleted animals differ from normal animals. By observing how disruption of a gene affects an animal’s growth, development, and health, we can develop insights into what that gene normally does in people as well as animals.

BHMT is an enzyme involved in the metabolism of dietary betaine and choline. This metabolic pathway is important because, among other things, it sustains the source of methyl donors necessary for DNA methylation. One of ways a gene can be controlled is by attaching methyl tags on top of it (to start or to stop it). When the Zeisel group created a type of mouse with the Bhmt gene deleted, they observed that (1) most of the mice would develop liver tumors within one year (Teng et al., 2011), and (2) prior to tumor development, the mice had better glucose tolerance and lower body fat (Teng et al., 2012). Since that time, the group has been trying to determine the mechanisms underlying these phenomena. One key question was “How will decreasing the main source of methyl donors change DNA methylation and, as a result, gene expression?” Understanding this effect could, in the long term, lead to ways to decrease risk of liver cancer, increase glucose tolerance, or lower body fat.

What they did: In their recent publication (Lupu et al., 2017), they found that deletion of Bhmt causes changes in the concentrations of certain metabolites and the extent of DNA methylation that are linked to altered gene expression in these mice. Specifically, the relative concentrations of metabolites S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) and DNA methylation in 63 regions (including one hotspot in chromosome 13) were altered and the expression of the gene Iqgap2 was reduced 378-fold. While they do not know yet how loss of methylation and decreased expression of Iqgap2 is related to tumor development, another group recently found that deletion of Iqgap2 also caused development of liver cancer (Gnatenko et al., 2013), suggesting that this association is not coincidental.

What it means: Taken together, Lupu et al.’s results suggest that Bhmt deletion causes a metabolite imbalance related to loss of DNA methylation that then alters normal gene expression. This altered gene expression is in some way associated with a higher risk of developing liver cancer. Liver cancer is the most rapidly increasing cancer in the United States. Notably, BHMT variations are common in humans and recent studies in human liver cancer showed that 93 percent of liver cancers have a BHMT gene variation. We don’t yet know which variations (if indeed any) increase risk of liver cancer. But liver cancer has a high mortality rate and is difficult to detect in its early stages. The potential association of Bhmt with liver cancer could reveal an identifiable and treatable risk factor. Thus, more detailed analysis could have far-reaching implications.

A second consequence of these findings is that they may aid in disentangling the beneficial metabolic effects of Bhmt deletion from the harmful effects. Bhmt deletion affects several metabolite concentrations, not just SAM and SAH. One or more of these other metabolites may be responsible for the observed improved glucose tolerance and weight maintenance, and this is also a continuing line of research in the laboratory.

Gnatenko DV, Xu X, Zhu W, Schmidt VA (2013). Transcript profiling identifies Iqgap2(-/-) mouse as a model for advanced human hepatocellular carcinoma. PLoS One. 8:e71826.

Lupu DS, Orozco LD, Wang Y, Cullen JM, Pellegrini M, Zeisel SH (2017). Altered methylation of specific DNA loci in the liver of Bhmt-null mice results in repression of Iqgap2 and F2rl2 and is associated with development of preneoplastic foci. FASEB J. [Epub ahead of print].

Teng YW, Ellis JM, Coleman RA, Zeisel SH (2012). Mouse betaine-homocysteine S-methyltransferase deficiency reduces body fat via increasing energy expenditure and impairing lipid synthesis and enhancing glucose oxidation in white adipose tissue. J Biol Chem. 287:16187-16198.

Teng YW, Mehedint MG, Garrow TA, Zeisel SH (2011). Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas. J Biol Chem. 286:36258-36267.