Toward defining the transcriptional ecosystem

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Rationale. Following environmental perturbations, cells must quickly react to ensure a proper gene response. Gene responses depend on transcription factor recruiting the transcription machinery and coregulators to regulatory regions. In the nucleus, the genome architecture creates proximity between regulatory regions of multiple genes forming local microenvironments. Recent evidence suggests that transcription coregulators are highly mobile within these enclosed microenvironments. This is conceptually reminiscent of ecosystems found in nature where multiple populations create dynamic interplays to share resources and maintain homeostasis. Whether or not a pool of transcription coregulators is assigned and traded between groups of connected genes is an open question. Objectives. The long-term goal of our research program is to demonstrate the existence of transcriptional ecosystem equilibriums between genes sharing the same physical environment. During the first 5 years, our goal will be to establish that transcription coregulators are mobile entities within a group of genes. Our central hypothesis is that transcription coregulators are traded between genes to sustain the response to environmental perturbations. To test our model, we are proposing two specific objectives: Objective 1 - Determine the response of group of genes to concomitant signals. Competition for resources is an important feature of natural ecosystems. Using environmental perturbations, we will investigate how group of genes react to concomitant signals. This will allow us to determine the presence of competitive and synergistic gene environments. Objective 2 - Establish the range of action of the transcriptional resources. Transcription machinery and coregulators are highly dynamic entities. We will use their mobility to identify connected genes sharing transcriptional resources. To do so, we will target the dCas9 fused to BirA to biotinylate proteins surrounding designated promoters and measure spreading to connected genes. Expected Outcomes. We will establish a new conceptual framework where genes are part of an ecosystem in which transcription coregulators are limiting and therefore travel from gene to gene. We will determine if competition for transcription machinery and coregulators exist which will be crucial to understand how a cell integrates concomitant signals. We will experimentally confirm the travelling of coregulators between genes. Lastly, we will determine if highly expressed genes are used as a transcriptional resources reservoir to sustain gene responses. Impact. With these discoveries, we will move our research field from semi-stable transcriptional models to biochemical equilibriums. This will redefine the notion of direct and indirect targets since a gene will not have to be directly occupied by an activated transcription factor to be regulated.