DNA Conformation Regulates Gene Expression: The MYC Promoter and Beyond

Abstract

Emerging evidence suggests that DNA topology plays an instructive role in cell fate control through regulation of gene expression. Transcription produces torsional stress, and the resultant supercoiling of the DNA molecule generates an array of secondary structures. In turn, local DNA architecture is harnessed by the cell, acting within sensory feedback mechanisms to mediate transcriptional output. MYC is a potent oncogene, which is upregulated in the majority of cancers; thus numerous studies have focused on detailed understanding of its regulation. Dissection of regulatory regions within the MYC promoter provided the first hint that intimate feedback between DNA topology and associated DNA remodeling proteins is critical for moderating transcription. As evidence of such regulation is also found in the context of many other genes, here we expand on the prototypical example of the MYC promoter, and also explore DNA architecture in a genome-wide context as a global mechanism of transcriptional control.

FUBP1 and FUBP2 enforce distinct epigenetic setpoints for MYC expression in primary single murine cells

“…Indeed, it has been shown that FUBP1 can contribute to a feedforward/feedback system that regulates Myc transcription in real-time. FUBP1 has been proposed to be a key effector that can both up- or downregulate MYC and behave as a molecular cruise control that opposes MYC fluctuations 29 , 32 , 45 , 69 . The superposition of multiple layers on Myc regulation might argue that its expression has been selected to be more tightly controlled than most other genes.…”

“…Of the multiple regions that regulate MYC expression, we have been interested in the far upstream element (FUSE), which is 1.7 kb upstream of the major P2 transcription start site of human MYC gene and binds FUBP1 23 , 29 – 36 . The FUSE-binding protein (FUBP) family has three members in human and mouse—FUBP1, FUBP2/KHSRP, and FUBP3 23 , 29 – 35 , 37 , 38 —and only one in Drosophil a—Psi 31 , 32 , 37 , 39 . FUBP1 is both prooncogenic and a tumor suppressor 37 , 40 , 41 .…”

“…The FUBPs all contain four repeated hnRNPK homology motifs in their central regions. Their central regions bind sequence selectively to either single-stranded DNA or RNA and the FUBPs have been reported to interact with various DNA or RNA targets and to participate in transcription, splicing, mRNA degradation, RNA transport, and translational regulation 29 , 31 , 32 , 34 – 38 , 42 , 43 . After FUSE melts in response to the torsional stress caused by dynamic supercoiling emanating from the Myc promoter, FUBP1 binds and loops to the promoter, interacting with TFIIH through the C-terminal domain of FUBP1 to activate transcription 44 , 45 .…”

“…The FUBP1-interacting repressor (FIR) may then be recruited by FUBP1 to inhibit the helicase activity of TFIIH, attenuating FUBP1 upregulation of Myc transcription 43 , 45 – 47 . Thus, the FUSE-FUBP-FIR system has been proposed to comprise a cruise control constraining MYC expression 29 , 31 , 32 , 45 , 48 – 50 by increasing MYC expression in some circumstances and decreasing it in others. Accordingly, when Fubp1 is knocked out in mice, both cell-to-cell and embryo-to-embryo Myc RNA levels fluctuate 51 .…”

The long noncoding RNA KCNQ1DN suppresses the survival of renal cell carcinoma cells through downregulating c-Myc

“…c-Myc is a conventional transcriptional factor. By binding to the cis- regulatory element E-box (CACGTG) of its transactivated genes, c-Myc plays an essential role in the regulation of many biological processes including cell cycle, cell proliferation, apoptosis and cell metabolism23-25. c-Myc has been reported to be upregulated in a variety of carcinomas including RCC.…”