The Bailis lab is focused on understanding how metabolism generates the biochemical networks that enforce immune cell state, by leveraging a CRISPR/Cas9 screening system compatible with gene editing in nearly every population of primary immune cells. This technology allows us to perform high-throughput reverse genetic screens, both in vitro and in in vivo adoptive transfer models, and interrogate metabolism at the network level to uncover the biochemical processes they regulate. Our work is currently focused in two main areas:
1) How does spatial compartmentalization of metabolism regulate immune cell state? Multicellular eukaryotes compartmentalize metabolic information at multiple levels. Within cells, biochemical reactions are separated by the organelles within which they occur; within tissues, metabolites can be divided between the cells that compose them; within an animal; different organ systems generate and consume distinct metabolic products that are shared throughout their host. We aim to elucidate how this biochemical partitioning is utilized by the immune system to regulate processes such cellular reprogramming during immune cell activation and how these cells sense and respond to alterations in tissue-level homeostasis.
2) How does biochemical state control immune cell signaling potential? In the context of immune cell activation, cellular metabolism is often understood to be one of many biological processes regulated downstream of classic signal transduction. From this top-down view, metabolism is a passive participant in cell reprogramming, acted upon by signaling pathways. There is now a large body of literature illustrating that metabolism can also act in a bottom-up fashion to regulate both signaling effectors as well as epigenetic modifications on the histones that control gene expression. In this manner, the biochemical potential of a cell has the capacity to tune both the quality and quantity of signaling that occurs as well as how that signal is received at target genes in the nucleus. We are actively investigating how metabolism influences post-translational modifications – the majority of which are derived from metabolites and/or generated by enzymes that use metabolites as cofactors – on signaling proteins (such as receptors and transcription factors) and histones.