RT Journal Article
SR Electronic
T1 Transcription factors use a unique combination of cofactors to potentiate different promoter-dependent steps in transcription
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.10.25.513774
DO 10.1101/2022.10.25.513774
A1 Charles C Bell
A1 Laure Talarmain
A1 Laura Scolamiero
A1 Enid YN Lam
A1 Ching-Seng Ang
A1 Omer Gilan
A1 Mark A Dawson
YR 2022
UL http://biorxiv.org/content/early/2022/10/25/2022.10.25.513774.abstract
AB Transcription factors use DNA binding domains to recognise specific sequences and transactivation domains to recruit the cofactor proteins necessary for transcription. However, how specific cofactors contribute to transactivation at different genes remains unclear. Here, we couple Gal4-transactivation assays with comparative CRISPR-Cas9 screens to identify the cofactors required by nine different transcription factors and nine different core promoters in human cells. We classify cofactors as ubiquitous or specific, discover novel transcriptional co-dependencies and demonstrate that submodules within large co-activator complexes, such as the tail 2 and kinase modules of Mediator, facilitate transcriptional elongation. Rather than displaying discrete mechanisms of action, we discover that each TF requires a unique combination of cofactors, which influence its ability to potentiate distinct steps in the transcriptional process. Our findings help reconcile models of cofactor-promoter compatibility by demonstrating that transcription at different classes of promoters is constrained by either initiation or pause release. These differences dictate cofactor compatibility and the dynamic range of gene expression. Overall, our screens provide insight into TF-cofactor relationships and their ability to potentiate different steps in transcription at different classes of promoters.Competing Interest StatementM.A.D. has been a member of advisory boards for GSK, CTX CRC, Storm Therapeutics, Celgene, and Cambridge Epigenetix and receives research funding from Pfizer.