(183ae) Decoding Phase Behavior of Human Transcription Factors through Systematic Classification and Simulations

Transcription factors (TFs) function as key regulators of gene expression by recognizing and binding to specific DNA sequences. This binding facilitates the recruitment of RNA polymerase and all other components of the transcriptional machinery to promoter sequences, thereby activating downstream gene expression. A TFs includes three functional regions or domains: a highly ordered DNA-binding domain and an effector domain (ED) region which is disordered. EDs usually contain an activation/repression domain responsible to regulate transcription and regions that interact with other regulatory proteins. A small extensively characterized set known as General Transcription Factors (GTFs) to bind to RNA polymerase II to form transcription initiation complexes enabling downstream gene transcription. The remainder set, specific transcription factors (STFs), regulate individual gene expression patterns and has a widely accepted classification based on the highly structured DNA-binding domain. The classification identifies several major families including zinc finger motifs, helix-turn-helix (HTH), leucine zipper regions (bZIP), homologous structural domains, and nuclear receptors—together accounting for more than 80% of human transcription factors. However, the set of 1,639 HTFs identified so far has not been fully studied and little is known about how they regulate transcription.

Many questions remain regarding how transcription factors regulate specific cellular processes, specifically in human diseases. The role of HTFs in maintaining cell types and lineages, evolution of normal cells to metastatic cancer, cellular signals that influence certain TF expression are just a few of the symptom-TF relation where little to nothing is known. A recently emerging field across TFs and intrinsically disordered proteins (IDPs) it is its ability to liquid-liquid phase separate. For example, OCT4 and GCN4 co-condensate with the Mediator coactivator and the RNAPII's C-terminal domain (CTD) phosphorylation state regulates its shuttling between condensates, coordinating transcription initiation and elongation. Further in vitro experiments have also shown condensation of disease-related TFs such as myc, p53 and the FET family of HTFs. Elucidating the phase behavior of TFs, its behavior in crowded environments and how condensation modifies the complex interaction network could lead to explain cellular nuclear dynamics and perhaps treating or preventing certain disorders like cancer, ALS or Alzheimer’s disease.