c-Myc regulates transcriptional pause release and is a global amplifier of transcription

Abstract

Elevated expression of the c-Myc transcription factor occurs frequently in human cancers and is associated with tumor aggression and poor clinical outcome. However, the predominant mechanism by which c-Myc regulates global transcription in both healthy and tumor cells is poorly understood. In this thesis, I present evidence that c-Myc is a global regulator of RNA Polymerase II (RNA Pol II) transcriptional pause release. Transcriptional pausing occurs when additional regulatory steps are required to promote elongation of genes after transcription has initiated. Chapter 2 identifies transcriptional pausing as a general feature of transcription by RNA Pol II in mammalian cells. c-Myc is identified as having a major role in promoting release from pause at its target genes. Chapter 3 finds in tumor cells with elevated c-Myc, the transcription factor binds to promoters and enhancers of most actively transcribed genes. The predominant effect of c-Myc binding is to produce higher levels of transcription by promoting RNA Pol II transcriptional pause release. Thus, c-Myc accumulates in the promoter regions of active genes across the cancer cell genome and causes transcriptional amplification, producing increased levels of transcripts within the cells gene expression program. These results imply that transcriptional amplification can reduce rate-limiting constraints for tumor cell growth and proliferation.