Ian M. Willis, Ph.D.
Signaling Pathways & Transcriptional Regulation in Growth Control and Metabolism
Our laboratory is conducting basic research on the mechanisms of eukaryotic transcriptional regulation in response to nutrients and environmental and cellular stress. We are especially interested in defining the signaling pathways and the mechanisms that regulate transcription of ribosomal components and transfer RNAs since these processes are critically important for controlling cell growth. Deregulation of cell growth control is widely recognized as a key event in cell transformation and tumorigenesis and is relevant to a broad range of human diseases. In addition, as the synthesis of new protein synthetic machinery constitutes >85% of nuclear gene transcription in growing cell populations, the tight coordinate control of this process, which involves all three nuclear RNA polymerases, is considered to be critical for metabolic economy and ultimately for cell survival. Our research programs span genetics, molecular biology, biochemistry and structural biology and utilize budding yeast, mammalian cells and mice as model experimental systems. Much of our current focus is on Maf1, a structurally and functionally novel protein that integrates the outputs of diverse signaling pathways and regulates transcription by all three nuclear RNA polymerases. Maf1 is also being studied because of its potential role as a tumor suppressor and as a regulator of metabolism. The conservation of Maf1 along with its downstream transcriptional targets and the signaling pathways that regulate Maf1 function facilitates the reciprocal translation of knowledge between yeast and mammalian systems and thereby promotes new discoveries.
Genetic Arrays, Gene Networks and Functional Genomics
Synthetic genetic array analysis and other systematic genome-wide genetic approaches such as synthetic dosage lethality and suppression are being applied using a first-of-its-kind robot to produce and replicate high density arrays of yeast. This technology enables the mapping of genetic interaction networks, defines the function of genes and establishes functional relationships between biochemical pathways. These genetic array-based approaches are being applied to a range of biological processes including transcriptional regulation as described above. The robot also serves as a resource to other researchers at AECOM and elsewhere who are working in yeast or in mammalian systems on genes that have homologs in yeast. The integration of genetic interaction data with other large scale datasets such as DNA microarray, ChIP-sequencing and protein-protein interaction data is used to inform testable hypotheses of the systems level behavior of genes and their products.
- Bonhoure N, Byrnes A, Moir RD, Hodroj W, Preitner F, et al. Loss of the RNA Polymerase III Repressor MAF1 Confers Obesity Resistance. Genes Dev. 2015 May 1;29(9):934-47.
- Lee J, Moir RD, Willis IM. Differential Phosphorylation of RNA Polymerase III and the Initiation Factor TFIIIB in Saccharomyces cerevisiae. PLoS One 2015 May 13;10(5):e0127225.
- Sanchez-Casalongue ME, Lee J, Diamond A, Shuldiner S, Moir RD, Willis IM. Differential Phosphorylation of a Regulatory Subunit of Protein Kinase CK2 by TOR Complex 1 Signaling and the Cdc-like Kinase Kns1. J Biol Chem. 2015 Mar 13;290(11):7221-33.
- Frame IJ, Deniskin R, Rinderspacher A, Katz F, Deng SX, et al. Yeast-Based High-Throughput Screen Identifies Plasmodium falciparum Equilibrative Nucleoside Transporter 1 Inhibitors That Kill Malaria Parasites. ACS Chem Biol. 2015 Mar 20;10(3):775-83.
- Bonhoure N, Bounova G, Bernasconi D, Praz V, Lammers F, et al. Quantifying ChIP-seq data: a spiking method providing an internal reference for sample-to-sample normalization. Genome Res. 2014 Jul;24(7):1157-68.
- Moir RD, Willis IM. Regulation of Pol III Transcription by Nutrient and Stress Signaling Pathways. Biochim Biophys Acta. 2013 Mar-Apr;1829(3-4):361-75.
- Moir RD, Gross DA, Silver DL, Willis IM. SCS3 and YFT2 link transcription of phospholipid biosynthetic genes to ER stress and the UPR. PLoS Genet. 2012 Aug;8(8):e1002890.
- Moir RD, Lee J, Willis IM. Recovery of RNA polymerase III transcription from the glycerol-repressed state: revisiting the role of protein kinase CK2 in Maf1 phosphoregulation. J Biol Chem. 2012 Aug 31;287(36):30833-41.
- Lee J, Moir RD, McIntosh KB, Willis IM. TOR signaling regulates ribosome and tRNA synthesis via LAMMER/Clk and GSK-3 family kinases. Mol Cell. 2012 Mar 30;45(6):836-43.
- Rana T, Misra S, Mittal MK, Farrow AL, Wilson KT, Linton MF, Fazio S, Willis IM, Chaudhuri G. Mechanism of down-regulation of RNA polymerase III-transcribed non-coding RNA genes in macrophages by Leishmania. J Biol Chem. 2011 Feb 25;286(8):6614-26.
- Bhattacharya A, McIntosh KB, Willis IM, Warner JR. Why Dom34 stimulates growth of cells with defects of 40S ribosomal subunit biosynthesis. Mol Cell Biol. 2010 Dec;30(23):5562-71.
- Lee J, Moir RD, Willis IM. Regulation of RNA polymerase III transcription involves SCH9-dependent and SCH9-independent branches of the target of rapamycin (TOR) pathway. J Biol Chem. 2009 May 8;284(19):12604-8.
- Willis IM, Chua G, Tong AH, Brost RL, Hughes TR, Boone C, Moir RD. Genetic interactions of MAF1 identify a role for Med20 in transcriptional repression of ribosomal protein genes. PLoS Genet. 2008 Jul 4;4(7):e1000112.
- Johnson AA, Zhang C, Fromm J, Willis IM Johnson DL. Mammalian Maf1 is a negative regulator of transcription by all three nuclear RNA polymerases. Mol Cell. 2007 May 11;26(3):367-79.
- Willis IM, Moir RD. Integration of nutritional and stress signaling pathways by Maf1. Trends Biochem Sci. 2007 Feb;32(2):51-3.
- Moir RD, Lee J, Haeusler RA, Desai N, Engelke DR, Willis IM. Protein kinase A regulates RNA polymerase III transcription through the nuclear localization of Maf1. Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15044-9.
- Sauve AA, Moir RD, Schramm VL, Willis IM. Chemical activation of Sir2-dependent silencing by relief of nicotinamide inhibition. Mol Cell. 2005 Feb 18;17(4):595-601.
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