Controlling the Master: Chromatin Dynamics at the MYC Promoter Integrate Developmental Signaling

Abstract

The transcription factor and cell growth regulator MYC is potently oncogenic and estimated to contribute to most cancers. Decades of attempts to therapeutically target MYC directly have not resulted in feasible clinical applications, and efforts have moved toward indirectly targeting MYC expression, function and/or activity to treat MYC-driven cancer. A multitude of developmental and growth signaling pathways converge on the MYC promoter to modulate transcription through their downstream effectors. Critically, even small increases in MYC abundance (<2 fold) are sufficient to drive overproliferation; however, the details of how oncogenic/growth signaling networks regulate MYC at the level of transcription remain nebulous even during normal development. It is therefore essential to first decipher mechanisms of growth signal-stimulated MYC transcription using in vivo models, with intact signaling environments, to determine exactly how these networks are dysregulated in human cancer. This in turn will provide new modalities and approaches to treat MYC-driven malignancy. Drosophila genetic studies have shed much light on how complex networks signal to transcription factors and enhancers to orchestrate Drosophila MYC (dMYC) transcription, and thus growth and patterning of complex multicellular tissue and organs. This review will discuss the many pathways implicated in patterning MYC transcription during development and the molecular events at the MYC promoter that link signaling to expression. Attention will also be drawn to parallels between mammalian and fly regulation of MYC at the level of transcription.

Keywords: DNA topology; Drosophila dMYC; FIR/Hfp; FUBP1/Psi; MYC; Mediator; TFIIH; development; signaling; transcription.

Figure 1

(1) For expression of MYC at basal levels, the pre-initiation complex (PIC) is assembled, consisting of the Mediator complex and general transcription factors (GTFs) which together recruit hypophosphorylated Pol II holoenzyme to be paused at the promoter. Recruitment of TFIIH promotes phosphorylation of Pol II at S5 residues. Upon activation by growth signals, chromatin is further remodeled, and downstream effector transcription factors (TFs) bind to enhancer elements, interacting with the MYC promoter via the Mediator complex, resulting in transcription and torsional strain on promoter, which promotes melting of the far upstream sequence element (FUSE) element. (2) In response to the growth signals, FUSE binding protein (FUBP1) recognizes and binds single-stranded FUSE, interacting with xeroderma pigmentosum type B (XBP) helicase subunit of TFIIH complex at the promoter and modulating nucleic acid architecture to facilitate exit of inhibitory cyclin-dependent kinase 8 (CDK8) module. Concurrently, bromodomain containing 4 (BRD4) interacts with the MYC promoter via Mediator complex, together with TFIIH promoting phosphorylation of Pol II at S2 residues. Thus, Pol II proceeds into productive elongation, and maximal expression of MYC is achieved. (3) FUBP1 recruits the FUBP-interacting repressor (FIR), which also binds to regulatory FUSE. FIR represses expression of MYC by negatively regulating TFIIH activity, reducing the rate of promoter escape by Pol II. (4) When the C-terminus of XPB is truncated due to mutations, interaction with FIR no longer occurs. Therefore, MYC promoter remains in a perpetual hyperactive state, increasing risk of tumourigenesis. TSS, transcription start site.