Tantin Lab :: Research
Greater than 10% of mammalian genes encode transcription factors. These transcription factors are used to achieve specific gene expression patterns. Because these patterns are critical for successful development and signal response, aberrations in transcription factor function frequently underlie human disorders such as cancer and immune dysfunction. Our laboratory employs biochemical, genetic and genomic approaches to determine transcription factor function in stem cells, in tumorigenesis, during lymphocyte development/function, and to elucidate specific gene regulatory circuits in normal and diseased cells. Our efforts focus on gene regulation both from the perspective of mechanisms of action and biological effects of specific transcription factors, as well as the means of coordinate and reciprocal regulation of specific groups of genes.
As an example, we are investigating the properties of an unusual class of homeodomain-related transcription factors that includes the stem cell master regulator Oct4. The prototypic member of this class is Oct1, which is widely expressed in adult cells. Oct2 expression is largely confined to B lymphocytes and the central nervous system. Oct1, Oct2 and Oct4 recognize the same consensus sequence. We have found that these proteins are signal integrators—coupling cellular metabolic, oxidative and genotoxic stress inputs to transcriptional output through protein phosporylation at conserved sites. These dynamic modifications are converted into a dynamic transcriptional response through changes in the ability to bind complex DNA sites as multimers. This is an active area of investigation in the laboratory.
Oct1 deficient cells have elevated reactive oxygen species (ROS) levels. Mitochondria are a major source of ROS and we have recently determined that loss of Oct1 alters metabolism such that glycolysis and lactate production are reduced while mitochondrial function is augmented. We are determining how Oct1 mediates these effects. The Oct1-mediated metabolic changes oppose those frequently encountered in stem cells and tumor cells, and we have now found that Oct1 controls transformation efficiency in vitro and tumorigenicity in vivo. Oct1 expression is also altered in human cancer.
Because Oct4 is a master regulator of stem cell identity, and because Oct1 and Oct2 share similar target specficity, post-translational modification sites and target genes, we are interested in determining 1) whether Oct1 and Oct2 can also regulate aspects of "stemness" in somatic tissues and cancer cells, and 2) whether Oct4 controls metabolism in the same manner as Oct1 in embryonic stem cells and whether "stemness" is in fact a metabolic phenomenon. We are also interested in how these proteins modulate gene expression and have identified a unique mechanism.
