Nuclear Synthesis of Acyl-CoAs in the Reprogramming of Chromatin and Gene Activity

• Applicant: Dr. Marta Russo
• Subject Area: General Genetics and Functional Genome Biology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 548812767

Metabolism and gene expression, two fundamental biological processes, are strongly interconnected and collaborate to regulate cellular functions and physiological activities. Metabolic enzymes and their byproducts, the metabolites, play crucial roles in modifying chromatin structure, thereby influencing gene expression. Traditionally, scientists have primarily focused on studying metabolic pathways in cellular compartments outside the nucleus, particularly in mitochondria. However, mounting evidence suggests the presence of metabolic enzymes within the nucleus, particularly those involved in acyl-coenzyme A (acyl-CoA) metabolism, which directly impacts histone modification. Recently, I discovered the existence of three metabolic enzyme complexes in the nuclei of mammalian cells, in addition to their known location in mitochondria. Significantly, these enzyme complexes interact with the Mediator complex, an essential facilitator of gene transcription by RNA Polymerase II. I demonstrated that these nuclear enzymes retain their functionality and capacity to produce their metabolites when bound to Mediator in the nucleus, while also enriching at Mediator target genes. Consequently, their products contribute to histone modification and gene expression regulation. This discovery proposes an intriguing hypothesis: metabolic enzymes within the nucleus regulate gene expression by producing metabolites. We believe this mechanism could be particularly relevant for cells like macrophages, immune cells that swiftly adjust their gene activity upon detecting danger signals. Nevertheless, essential molecular details concerning the interplay between nuclear metabolic enzymes and the transcriptional machinery remain unclear. Hence, my objectives are: 1) to investigate the influence of these nuclear enzymes on gene regulation; 2) to identify novel protein interactions of these enzymes in the nucleus; and 3) to analyze the structure of these enzymes and their interactions with the Mediator complex. By employing advanced omics-based approaches, metabolite tracing and imaging techniques, my research aims to elucidate the functional dynamics and structural characteristics of these interactions. Macrophages will serve as the principal cellular model due to their rapid adjustments in gene expression and metabolic reprogramming in response to danger signals. In summary, the proposed research aims to provide insights into the crucial interplay between metabolism and transcriptional regulation, elucidating the role of nuclear metabolic enzymes in gene regulation.

• DFG Programme: Emmy Noether Independent Junior Research Groups