A novel role for the pol I transcription factor UBF in the regulation of expression of histone gene clusters and cellular DNA damage responses

Transcription of the 200 copies of ribosomal RNA (rRNA) genes by RNA Polymerase I (Pol I) is one of the most energy consuming processes and its dysregulation is a consistent feature of cancer. One of the most important ongoing questions is understanding how Pol I is coupled to distinct Pol II transcription programs in normal and tumour cells.

We have recently identified novel roles for the Pol I chromatin remodelling factor UBF. We demonstrated using chromatin immunoprecipitation (ChIP) sequencing that UBF is enriched at 1700 genes. Analysis of the genes bound by UBF and are differentially expressed following UBF knockdown suggests that UBF regulates genes associated with chromatin assembly including histone genes. In silico Motif analysis suggest that the oncogene c-MYC may cooperate with UBF to regulate histone gene expression. This project aims to explore this hypothesis by performing ChIP assays to confirm that c-MYC is bound at the sites of UBF enrichment in histone genes. Further, this project aims to examine a model of spontaneous MYC driven lymphomas (Eμ-Myc) in which MYC is overexpressed in lymphocytes to explore the dependencies between UBF regulation of histone gene expression and tumour progression.