Identification and functional characterization of transcriptional activators in human cells.
Transcription is orchestrated by thousands of transcription factors (TFs) and chromatin-associated proteins, but how these are causally connected to transcriptional activation is poorly understood. Here, we conduct an unbiased proteome-scale screen to systematically uncover human proteins that activate transcription in a natural chromatin context. By combining interaction proteomics and chemical ... inhibitors, we delineate the preference of these transcriptional activators for specific co-activators, highlighting how even closely related TFs can function via distinct cofactors. We also identify potent transactivation domains among the hits and use AlphaFold2 to predict and experimentally validate interaction interfaces of two activation domains with BRD4. Finally, we show that many novel activators are partners in fusion events in tumors and functionally characterize a myofibroma-associated fusion between SRF and C3orf62, a potent p300-dependent activator. Our work provides a functional catalog of potent transactivators in the human proteome and a platform for discovering transcriptional regulators at genome scale.
Mesh Terms:
Animals, Cell Cycle Proteins, Cell Line, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Intercellular Signaling Peptides and Proteins, K562 Cells, Mice, Myofibroma, NIH 3T3 Cells, Proteome, Proteomics, Serum Response Factor, Transcription Factors, Transcription, Genetic, Transcriptional Activation
Animals, Cell Cycle Proteins, Cell Line, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Intercellular Signaling Peptides and Proteins, K562 Cells, Mice, Myofibroma, NIH 3T3 Cells, Proteome, Proteomics, Serum Response Factor, Transcription Factors, Transcription, Genetic, Transcriptional Activation
Mol Cell
Date: Dec. 03, 2021
PubMed ID: 35016035
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