Abstract Research over the last decades has uncovered epigenetic mechanisms that precisely regulate the genome. For instance, histone post-translational modifications (PTMs) shape the local chromatin landscape of human cells to establish permissive and repressive regions within the genome to orchestrate DNA transcription, replication, and repair. Nevertheless, there is still a great deal that we do not understand about how the cell integrates signals from inside and outside itself to coordinate proper gene expression. In addition to the classic signaling pathways that couple metabolism to transcription (e.g., nuclear receptors, kinases), chromatin directly “senses” metabolic status through the availability of metabolites that are converted to histone PTMs. Since metabolic dysregulation is a component of nearly every disease, understanding how these altered metabolic pathways impact epigenetic regulation and vice versa is critical for developing new and effective disease interventions. However, the incredible complexity and dynamic nature of metabolic pathways and chromatin PTM signaling has made it difficult to characterize the molecular-level details of this link between metabolism and chromatin. To tackle this problem, my lab is creating novel chemical tools to determine how a particular subset of histone PTMs called acylations are regulated by acyl-CoA metabolism and how these PTMs lead to specific effects on gene expression. We are developing acyl-CoA biosensors to determine how acyl-CoA dynamics change in response to cellular conditions and how compartmentalization of acyl-CoA metabolism occurs, particularly with respect to the nuclear compartment and histone acylation. Moreover, our biosensors will similarly expand our understanding of acyl-CoA metabolism under both normal and disease conditions and will enable the identification of the acyl-CoA-producing enzymes and acyltransferases that regulate specific histone acylations. To determine how histone acylations impact gene expression, we are developing affinity-based probes to identify proteins that bind to histone acylations. By identifying these binding proteins, we will be able to assign specific gene regulatory functions to these PTMs. With this information, we will be able to develop new therapeutic strategies to intercept communication between metabolism and the genome at the acyl-CoA and histone acylation levels to precisely reprogram these signaling pathways in disease.