Role of the Paf complex for the control of transcription by Drosophila Myc
Final Report Abstract
We are using Drosophila melanogaster as a model system to investigate the molecular mechanisms that control animal growth during normal and pathological development. Our main focus is the transcription factor and proto-oncogene Myc, which is a major regulator of these processes. By combining ChIPseq and RNAseq approaches in Drosophila tissue culture cells we identified a core set of a few hundred Myc target genes, whose salient function resides in the control of ribosome biogenesis. Amongst these genes we found the non-coding snoRNA genes as a large novel class of Myc targets. All assayed snoRNAs are affected by Myc, and many of them are subject to direct transcriptional activation by Myc, both in Drosophila and in vertebrates. The loss of snoRNAs impairs growth during normal development, whereas their overexpression increases tumor mass in a model for neuronal tumors. In combination with recent observations of snoRNA involvement in human cancer, this raises the possibility that some of Myc’s transforming effects are mediated by this class of non-coding transcripts. Many of the Myc targets we identified here carry a well established Myc binding site in their promoter region, a so called E-box. However, E-box variants occur more than 170'000 times throughout the Drosophila genome, often far away from promoters. It is unclear why Myc preferentially recognizes E-boxes located in promoter-proximal positions, and how Myc interacts with targets lacking any E-boxes. Our work provides a partial answer to this question: we identified the general transcription factor Leo1, a component of the PAF1 elongation factor complex, as a novel Myc interacting protein. Since the PAF1 complex is typically associated with active genes, the binding to Leo1 contributes to Myc targeting to active promoters, both with and without E-boxes. Depletion of Leo1 significantly reduces Myc's association with promoters, affects the expression of direct Myc targets and compromises Myc-dependent processes in vivo. While these investigations identify Leo1 as another factor that helps recruit Myc to its target genes, they also suggest the existence of additional hitherto unidentified factors that fulfill similar roles.
Publications
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(2013). Myc Function in Drosophila. Cold Spring Harb Perspect Med 3 (10), a014324
P. Gallant
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(2014). Drosophila mbm is a nucleolar myc and casein kinase 2 target required for ribosome biogenesis and cell growth of central brain neuroblasts. Mol. Cell. Biol. 34, 1878-1891
A. Hovhanyan, E.K. Herter, J. Pfannstiel, P. Gallant, T. Raabe
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(2015). snoRNAs are a novel class of biologically relevant Myc targets. BMC Biology 13, 25
E.K. Herter, M. Stauch, M. Gallant, E. Wolf, T. Raabe, P. Gallant
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PAF1 complex component Leo1 helps recruit Drosophila Myc to promoters. PNAS October 31, 2017 114 (44) E9224-E9232
J.M. Gerlach, M. Furrer, M. Gallant, D. Birkel, Apoorva Baluapuri, Elmar Wolf, P. Gallant
