Dissecting transcriptional amplification by MYC

• DOI: 10.7554/elife.52483
• Publication Date: 2020-07-27T09:00:19Z
• Authors: Zuqin Nie; Chunhua Guo; Subhendu K Das; Carson C Chow; Eric Batchelor; S Stoney Simons; David Levens
• Keywords: Transcriptional Activation; 0301 basic medicine; kinetic mechanism of action; QH301-705.5; Science; Q; R; Gene Amplification; general amplifier; michaelis-menten kinetics; MYC; Cell Line; Rats; Proto-Oncogene Proteins c-myc; 03 medical and health sciences; cancer; Medicine; Animals; Humans; Biology (General); transcription; Cancer Biology; Transcription Factors

SupraphysiologicalMYClevels are oncogenic. Originally considered a typical transcription factor recruited to E-boxes (CACGTG), another theory posits MYC a global amplifier increasing output at all active promoters. Both models rest on large-scale genome-wide ”-omics’. Because the assumptions, statistical parameter and model choice dictates the ‘-omic’ results, whether MYC is a general or specific transcription factor remains controversial. Therefore, an orthogonal series of experiments interrogated MYC’s effect on the expression of synthetic reporters. Dose-dependently, MYC increased output at minimal promoters with or without an E-box. Driving minimal promoters with exogenous (glucocorticoid receptor) or synthetic transcription factors made expression more MYC-responsive, effectively increasing MYC-amplifier gain. Mutations of conserved MYC-Box regions I and II impaired amplification, whereas MYC-box III mutations delivered higher reporter output indicating that MBIII limits over-amplification. Kinetic theory and experiments indicate that MYC activates at least two steps in the transcription-cycle to explain the non-linear amplification of transcription that is essential for global, supraphysiological transcription in cancer.