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  • Ian M. Willis, Ph.D.

Ian M. Willis, Ph.D.

Ian M. Willis

Professor, Department of Biochemistry

Professor, Department of Systems & Computational Biology

Area of Research: RNA polymerase III transcription and its repression by Maf1; Mechanisms of obesity resistance in Maf1 knockout mice; Mechanisms of neurodegeneration in Pol III-related leukodystrophy

Contact Information

718.430.2839ian.willis@einsteinmed.edu

Albert Einstein College of Medicine
Jack and Pearl Resnick Campus

1300 Morris Park Avenue
Forchheimer Building, Room 316
Bronx, NY 10461

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Professional Interests

RNA Polymerase III Transcription in Health and Disease

Our laboratory studies gene transcription by RNA polymerase (Pol) III and the functional impact of this system on normal and disease processes. The products of Pol III transcription are small non-coding RNAs that have diverse and expanding functions in eukaryotic cells. These include RNAs that are central players in cell growth, notably in protein synthesis, and molecules that function in RNA processing, protein secretion and in various regulatory capacities.  Proper regulation of Pol III transcription is critical for balanced growth and its deregulation is a key event in cell transformation and tumorigenesis.  For these and other reasons, much of our research has focused on the Maf1 protein, a master negative regulator of Pol III transcription, and its posttranslational control by nutrient- and stress-signaling pathways. Our programs span genetics, molecular biology, biochemistry, metabolism and structural biology and utilize budding yeast and mice as model experimental systems. Two important areas of concentration are highlighted below.

Mechanisms of Obesity Resistance in Maf1 Knockout Mice

Mice with a whole body knockout of Maf1 are resistant to diet-induced obesity and have increased healthspan. Obesity resistance in these mice is associated with increased energy expenditure and metabolic inefficiency. Our current mechanistic understanding of these phenotypes is based on a novel futile RNA cycle hypothesis wherein deregulated Pol III transcription serves as an energy sink, consuming energetically costly nucleotides in the wasteful synthesis of RNA that does not accumulate and is mostly degraded. Current research on this unique model is focused on understanding global (whole body) and cell-specific molecular and metabolic changes that enhance energy expenditure and contribute to the lean phenotype.  We are also exploring the possibility that MAF1 may be targeted therapeutically to treat obesity and improve healthspan.

Mechanisms of Neurodegeneration in Pol III-related Leukodystrophy

Pol III-related leukodystrophy was recently identified as a genetically inherited neurodegenerative disease.  The early-onset form of the disease manifests in children as a progressive decline in motor function, cognitive regression and intellectual disability with variable neurological and non-neurological features.  We have developed a mouse model of this disease and have characterized numerous behavioral and neuropathological phenotypes. Our research seeks to understand the mechanisms of pathogenesis in different neural cell populations and their molecular basis. The work is currently focused on the oligodendrocyte lineage since hypomyelination is a hallmark of the disease in patients and in the mice.  


Selected Publications

  • Merheb E, Cui MH, DuBois JC, Branch CA, Gulinello M, Shafit-Zagardo B, Moir RD, Willis IM. Defective myelination in an RNA polymerase III mutant leukodystrophic mouse. Proc Natl Acad Sci U S A. 2021 Oct 5;118(40):e2024378118.
  • Moir RD, Lavados C, Lee J, Willis IM. Functional characterization of Polr3a hypomyelinating leukodystrophy mutations in the S. cerevisiase homolog, RPC160. Gene. 2021 Feb 5;768:145259.
  • Vorländer MK, Baudin F, Moir RD, Wetzel R, Hagen WJH et al. Structural basis for RNA polymerase III transcription repression by Maf1. Nat. Struct. Mol. Biol., 2020 Mar; 27(3):229-232.
  • Choquet K, Pinard M, Yang S, Moir RD, Poitras C et al. The leukodystrophy mutation Polr3b R103H causes homozygote mouse embryonic lethality and impairs RNA polymerase III biogenesis. Mol Brain. 2019 Jun 20;12(1):59.
  • Willis, IM, Moir RD, Hernandez, N. Metabolic Programing a Lean Phenotype by Deregulation of RNA Polymerase III. Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):12182-12187. 
  • Willis IM, Moir RD. Signaling to and from the RNA polymerase III Transcription and Processing Machinery. Annu. Rev. Biochem. 2018 Jun 20;87:75-100.
  • Willis IM. Maf1 Phenotypes and Cell Physiology. Biochim Biophys Acta Gene Regul Mech. 2018 Apr;1861(4):330-337.
  • Choquet K, Yang S, Moir RD, Forget D, Larivière R et al. Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation. Mol Brain. 2017 Apr 13;10(1):13.
  • Mange F, Praz V, Migliavacca E, Willis IM, Schütz F, Hernandez N, CycliX Consortium. Diurnal regulation of RNA polymerase III transcription is under the control of both the feeding-fasting response and the circadian clock. Genome Res. 2017 Jun;27(6):973-984.
  • 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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