Defining the mTORC1-dependent signaling mechanisms mediating epigenetic modifications

Cells and organisms must coordinate their metabolic activity with changes in their nutrient environment. This is achieved via signaling networks that integrate the sensing of local and systemic nutrients and relay nutrient status to the control of cellular anabolic and catabolic processes. Aberrant activation of the mTORC1 signaling network (mechanistic Target of Rapamycin Complex I) underlies the development and progression of LAM. However, the molecular and pathological consequences of this activation are still largely unknown due, in part, to a lack of understanding of the downstream cellular processes regulated by mTORC1. As demonstrated by our previous studies, cells deficient for the TSC (Tuberous Sclerosis Complex) complex exhibit an mTORC1-dependent increase in metabolic flux through the de novo pyrimidine and purine synthesis pathways (Ben-Sahra et al., Science 2013 and Science 2016) . Nucleotide molecules are essential to maintain cellular homeostasis and to produce macromolecules required to sustain cell growth and proliferation. Chromatin modifications have been well-recognized to play a critical role in the regulation of genome function. Many of these modifications are introduced and removed by enzymes that utilize molecules derived from cellular metabolism. Given that mTORC1 is a key regulator of diverse metabolic processes, we hypothesize that this signaling pathway as well as nucleotide metabolism can also impinge on epigenetic modifications indirectly through regulation of LAM cell metabolism and/or directly through regulation of epigenetic modulators. The critical significance of closely connecting the TSC-mTORC1 network to metabolic signals and epigenetics events in human health is highlighted by the fact that aberrant epigenetic modifications could be implicated in the pathophysiology of several types of cancers and LAM. The research under this proposal is aimed at defining the molecular mechanisms and consequences of epigenetics regulation downstream of the mTORC1 signaling network. We hope that the findings from this proposal will impact our understanding and, perhaps, outline potential strategies that target crosstalks between mTORC1 induced-epigenome and metabolome alterations that might be exploited to selectively eradicate LAM progression