Metabolic enzymes in gene control

Cellular compartments are believed to serve functional separation within the cell and allow it to perform multiple metabolic processes at the same time. Processes are divided between compartments with respect to the physiological requirements for a certain process. Thus, regulatory processes involving chromatin organization and control of gene activity are performed in the nucleus while metabolic processes are believed to be performed in the aqueous cytoplasm and cytoplasmic organelles. Numerous reports demonstrate that transcriptional modulation has a strong impact on metabolism, as expression levels of metabolic enzymes are limited by signaling pathways and the transcriptional machinery (Blanchet et al., 2011; Desvergne et al., 2006; Dufour et al., 2011). On the other hand, there should be mechanisms allowing feedback control from metabolism to gene expression that would tune the transcriptional program of the cell in accordance with its physiological needs (McKnight, 2010; Ray, 2010). Essentially, metabolic flux, including metabolic enzymes, small metabolites, nutrients and redox state, should impose reciprocal control upon nuclear events. However, there is little knowledge on mechanisms that allow such regulation. In recent years, several groups addressed this question and discovered that concentrations of intermediate metabolites indeed affect gene control (Shi, 2004). In all cases, metabolic compounds such as NADH, Acetyl-CoA and poly-ADP ribose bind to chromatin and change gene activity. Potentially many more metabolites should touch upon the gene expression machinery. These “metabolic” regulatory complexes might, in turn, affect expression of the transcriptional regulators of metabolism and close the feedback loop.