Mechanism and Scaling of Eukaryotic Transcription Activation

Transcription activation is a universal process by which living cells adapt. Decades of work in this field have produced an intelligible paradigm of transcription activation that provides fundamental insights into its underlying molecular mechanisms. This thesis attempts to extend such paradigm to explain how transcription activation can be implemented across the diversity of molecular environments found in eukaryotic nuclei. Specifically, this diversity calls for an explanation of how this process scales throughout a range of genome sizes that spans five orders of magnitude, and of how to think about this subject in the increasingly relevant context of liquid-liquid phase-separation. We leverage data from RNA-seq, smFISH, growth-rate, fluorescence microscopy, computer simulations and literature to identify an appropriate and useful level of abstraction in which to grow our current paradigm. We propose scaling and phase-separation, two seemingly disparate aspects of transcription, are explained and intrinsically linked by a novel molecular state in which multiple RNA polymerases can bind the transcription complex. We provide support and rationale for this addition to the transcription model, and generate testable hypotheses that may further clarify the mechanism and evolution of eukaryotic transcription activation.