Taming of the beast: shaping Myc-dependent amplification

Abstract

Myc deregulation is a hallmark oncogenic event where overexpression of the transcription factor gives rise to numerous tumorigenic phenotypes. The complex consequences of Myc deregulation have prevented clear mechanistic interpretations of its function. A synthesis of recent experimental observations offers a consensus on the direct transcriptional function of Myc: when overexpressed, Myc broadly engages the established euchromatic cis-regulatory landscape of the cell, where the factor generally amplifies transcription. The level of Myc binding at target genes and the transcriptional output are differentially modulated by additional regulators, including Miz1. Targeting Myc oncogenic activity will require an understanding of whether amplification promotes tumorigenesis and the consequences of amplification in tumors adapted to oncogenic Myc.

Keywords: Myc; cancer; transcription.

Figure 1. Schematic of MYC’s transcription elongation promoting activity

MYC/MAX bind to E-box (CACGTG) sequences at enhancers and promoters and recruits the elongation factor complex P-TEFb, which promotes elongation in part by phosphorylating the C-terminal domain of RNA Polymerase II.

Figure 2. Schematic of MYC genomic binding at (A) low, (B) medium, and (C) high concentrations of the factor

Cis-regulatory elements (boxes) are shaded by their affinity for Myc. Myc transcriptional activity at genes is depicted as a circle sized by Myc’s impact.

Figure 3. Schematic showing the dynamic occupancy of E-box sites by Myc and other transcriptional regulators

Multiple bHLH transcription factor pairings compete for binding at E-box sites. The net positive or negative transcriptional consequence of regulator binding at E-boxes is depicted.

Figure 4. Schematic of Myc transfer functions

Transfer functions are shown providing the relationship between expression changes at genes as a function of various parameters as measured either by absolute or relative change in expression. (A) A linear amplifier transfer function where the change in expression in high vs. low Myc conditions is constant across all transcriptionally active genes. (B) A non-linear amplifier transfer function where the change in expression in high vs. low Myc conditions is proportional to the exponent of the expression in low Myc conditions. (C) A Myc/Miz1 repression transfer function where the change in expression is proportional to the ratio of ΔMyc binding divided by Miz1 binding. (D) A combined Miz1 shaped non-linear amplifier model that combines the transfer functions in (B) and (C). A two dimensional heatmap is provided showing the relative change in expression as a function of both the ratio of ΔMyc binding divided by Miz1 binding (y-axis) and the initial expression in low Myc conditions (x-axis).