Talk abstracts
Talk on Saturday 10:30-10:45am submitted by Dervla Moore-Frederick
RNA-binding proteins activate transcription through defined molecular grammars
Dervla Moore-Frederick (Department of Biological Sciences, Carnegie Mellon University), Haoran Wang, Lydia Phillips (Department of Biological Sciences, Carnegie Mellon University), Bailey Webster, Deyuan Xu, Arth Banka, Grant Mowry, Emily Wang (Department of Biological Sciences, Carnegie Mellon University), Sid Srivastava (Department of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA), Jonathan E Henninger (Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA)
Abstract:
RNA molecules transcribed from enhancers and promoters regulate transcription at genes, in some cases by interacting with transcription factors (TFs) and cofactors. RNA-binding proteins (RBPs) also bind nascent RNAs to orchestrate co-transcriptional RNA processing, so we wondered if some of these RBPs could moonlight as transcriptional regulators independent of their roles in RNA processing. Here, we screened dozens of chromatin-associated RBPs in cellular transcription assays and identified 13 that activate transcription. Activators included splicing-associated RBPs such as HNRNPA1, HNRNPH1, RBM22 and SF1, as well as known transcriptional regulators FUS, EWSR1, and TDP43. Like classical TFs, RBPs regulate distinct genes involved in cell identity and partition into transcriptional condensates. Compared with non-activators, RBP activators are enriched in aromatic and polar residues but depleted of charged residues – mirroring established TF activation domains. These enrichments are conserved and essential for RBP-mediated activation. We used these molecular grammar rules to predict additional RBP activators from the human proteome and selected 9 factors, each of which activated transcription in our assays. The C-terminal domain (CTD) of RPB1, the largest subunit of RNAP2, was among these activators, which suggests that non-transcribing RNAP2 complexes near genes function to positively regulate transcription. Using a chemical dimerizer system, we found that synthetic CTD condensates in cells could recruit endogenous Mediator coactivator, consistent with a non-enzymatic function for RPB1 in transcription. Together, our findings uncover a noncanonical role for RNA-processing factors in direct transcriptional regulation and reveal RNA-RBP regulatory networks that parallel classic DNA-TF networks.
Keywords: RNA-binding proteins, transcriptional regulation, biomolecular condensates