Epidermal Gene Regulation

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Leah Vardy

Leah Vardy received her Ph.D at the Imperial Cancer Research Fund in London in the laboratory of Takashi Toda. Her work investigated the role of three microtubule organizing center components in mitotic progression and checkpoint control. Following this she started her post-doctoral work with Terry Orr-Weaver at the Whitehead Institute in Cambridge, in the US. There she worked with Drosophila to study the mechanisms by which translation of the mitotic cyclins is temporally controlled during oogenesis and in early embryos. In 2007, she was appointed to IMB and spent a year at the Genome Institute of Singapore studying global translational controls in ES cells. Leah moved to the IMB in July 2008 to continue this line of research. Her current interests lie in understanding gene expression control in embryonic stem cells and in the epidermis.

Post-transcriptional control in embryonic stem cells and the epidermis.
Post-transcriptional control plays a significant role in regulating gene expression and protein production. Disruption of these controls is associated with a wide range of diseases and disorders and can affect splicing, RNA stability or RNA translation.  Post-transcriptional control is mediated in part by trans-acting factors in the form of miRNAs and RNA binding proteins that bind to cis-acting sequences in the RNA to regulate their fate in an mRNA specific manner. More recently ribosomal proteins have been shown to regulate translation of specific mRNAs.  We are interested in understanding these controls in embryonic stem cells and in the epidermis. 

EMBRYONIC STEM CELLS: We are working to understanding the role of miRNAs in regulating differentiation of ESCs to neural stem cells. 

EPIDERMIS: We are exploring the function of ribosomal proteins in the epidermis and determining their role in keratinocyte function.  

Polyamine mediated regulation in the epidermis. 
The polyamines are ubiquitously expressed cations that are essential for many cellular processes. The diamine putrescine and the polyamines spermidine and spermine are synthesised in the cell or imported from the extracellular environment. Their levels are very tightly controlled largely by two rate limiting enzymes ODC1 and AMD1. ODC1 is required for the formation of putrescine from ornithine and AMD1 provides the amino propyl donor for the formation of spermidine and spermine from putrescine. Manipulation of the levels or activities of these two enzymes influences both the level and ratio of the three polyamines.  Polyamines are required for a wide array of cellular processes and can regulate gene expression at a gene specific level. Due to their positive charge they are largely associated with RNA and DNA. They have been shown to impact on transcription, translation, RNA stability and splicing in different cellular contexts. We are exploring the role of the polyamine regulators AMD1 and ODC1 in embryonic stem cell (ESC) differentiation and in the epidermis. 

EMBRYONIC STEM CELLS: We recently described an essential role for AMD1 in mouse ESC self-renewal and are currently working to identify the down-stream targets of the polyamines that promote self-renewal.  We are investigating how these genes are controlled by the polyamines and how they are functioning to promote self-renewal.

EPIDERMIS: We are addressing the role of AMD1 in the formation of the skin barrier and in the function of human keratinocytes during proliferation, migration and differentiation.  

Group Members

Research Fellows Lim Hui Keng
  Aishwarya Sridharan
Postgraduate Student Anisa Rahim 
Research Officers
Christina James
Vonny Leo
  Nazreen Muthaliff

James C, Zhao TY, Rahim A, Saxena P, Muthalif NA, Uemura T, Tsuneyoshi N, Ong S, Igarashi K, Lim CY, Dunn NR, Vardy LA. MINDY1 is a Downstream Target of the Polyamines and Promotes Embryonic Stem Cell Self-Renewal. Stem Cells. 2018 Apr 12. doi: 10.1002/stem.2830 Link
Kheng LH, Rahim AB, Leo VI, Shatarupa D, Lim TC, Uemura T, Igarashi K, Common J, Vardy LA. Polyamine regulator AMD1 promotes cell migration in epidermal wound healing. J Invest Dermatol. 2018 Jun 12. pii: S0022-202X(18)32058-X. doi: 10.1016/j.jid.2018.05.029 Link
Martinez EC, Lilyanna S, Wang P, Vardy LA, Jiang X, Armugam A, Jeyaseelan K, Richards AM. MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease. J Mol Cell Cardiol. 2017 Nov;112:27-39. doi: 10.1016/j.yjmcc.2017.08.013 Link
Cui X, Liang Z, Shen L, Zhang Q, Bao S, Geng Y, Zhang B, Leo V, Vardy LA, Lu T, Gu X, Yu H. 5-Methylcytosine RNA Methylation in Arabidopsis Thaliana. Mol Plant. 2017 Nov 6;10(11):1387-1399. doi: 10.1016/j.molp.2017.09.013 Link
Carlevaro-Fita J, Rahim A, Guigó R, Vardy LA, Johnson R. Cytoplasmic long noncoding RNAs are frequently bound to and degraded at ribosomes in human cells. RNA. 2016 Jun;22(6):867-82. doi: 10.1261/rna.053561.115. Link
Wong QW, Vaz C, Lee QY, Zhao TY, Luo R, Archer SK, Preiss T, Tanavde V, Vardy LA. Embryonic Stem Cells Exhibit mRNA Isoform Specific Translational Regulation. PLoS One. 2016 Jan 22;11(1):e0143235. doi: 10.1371/journal.pone.0143235. Link
Rahim AB, Vardy LA. Analysis of mRNA Translation Rate in Mouse Embryonic Stem Cells. Methods Mol Biol. 2016;1341:143-55. doi: 10.1007/7651_2015_233. Link
Giannakakis A, Zhang J, Jenjaroenpun P, Nama S, Zainolabidin N, Aau MY, Vaz C, Ivshina AV, Voorhoeve M, Vardy LA, Sampath P, Kuznetsov VA, Kurochkin IV, Guccione E. “Contrasting expression patterns of coding and noncoding parts of the human genome upon oxidative stress.” Sci Rep. 2015 May 29;5:9737. doi: 10.1038/srep09737.
Wong LL, Wee AS, Lim JY, Ng JY, Chong JP, Liew OW, Lilyanna S, Martinez EC, Ackers-Johnson MA, Vardy LA, Armugam A, Jeyaseelan K, Ng TP, Lam CS, Foo RS, Richards AM, Chen YT. “Natriuretic peptide receptor 3 (NPR3) is regulated by microRNA-100.” J Mol Cell Cardiol. 2015 Feb 28;82:13-21. doi: 10.1016/j.yjmcc.2015.02.019.
Tan SM, Altschuler G, Zhao TY, Ang HS, Yang H, Lim B, Vardy L, Hide W, Thomson AM, Lareu RR. Divergent LIN28-mRNA associations result in translational suppression upon the initiation of differentiation. Nucleic Acids Res. 2014 Jul;42(12):7997-8007. doi: 10.1093/nar/gku430. Epub 2014 May 23. PubMed PMID: 24860167; PubMed Central PMCID: PMC4081066. Link
Wong QW, Li J, Ng SR, Lim SG, Yang H, Vardy LA. RPL39L is an example of a recently evolved ribosomal protein paralog that shows highly specific tissue expression patterns and is upregulated in ESCs and HCC tumors. RNA Biol. 2014 Jan;11(1):33-41. doi: 10.4161/rna.27427. Epub 2013 Dec 20. PubMed PMID: 24452241; PubMed Central PMCID: PMC3929422. Link
Kotoshiba S, Gopinathan L, Pfeiffenberger E, Rahim A, Vardy LA, Nakayama K, Nakayama KI, Kaldis P. p27 is regulated independently of Skp2 in the absence of Cdk2. Biochim Biophys Acta. 2014 Feb;1843(2):436-45. doi: 10.1016/j.bbamcr.2013.11.005. Epub 2013 Nov 21. PubMed PMID: 24269842; PubMed Central PMCID: PMC3915056. Link
Courtes FC, Vardy L, Wong NS, Bardor M, Yap MG, Lee DY. Understanding translational control mechanisms of the mTOR pathway in CHO cells by polysome profiling. N Biotechnol. 2014 Sep 25;31(5):514-23. doi: 10.1016/j.nbt.2013.10.003. Epub 2013 Oct 22. PubMed PMID: 24157712. Link
Ramot Y, Vardy LA. Commentary on: Hairless and the polyamine putrescine form a negative regulatory loop in the epidermis. Exp Dermatol. 2013 Nov;22(11):697-8. doi: 10.1111/exd.12244. PubMed PMID: 24433178. Link
Courtes FC, Lin J, Lim HL, Ng SW, Wong NS, Koh G, Vardy L, Yap MG, Loo B, Lee DY. Translatome analysis of CHO cells to identify key growth genes. J Biotechnol. 2013 Sep 10;167(3):215-24. doi: 10.1016/j.jbiotec.2013.07.010. Epub 2013 Jul 19. PubMed PMID: 23876478. Link
Bezzi M, Teo SX, Muller J, Mok WC, Sahu SK, Vardy LA, Bonday ZQ, Guccione E. Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery. Genes Dev. 2013 Sep 1;27(17):1903-16. doi: 10.1101/gad.219899.113. PubMed PMID: 24013503; PubMed Central PMCID: PMC3778243. Link
Dreesen O, Chojnowski A, Ong PF, Zhao TY, Common JE, Lunny D, Lane EB, Lee SJ, Vardy LA, Stewart CL, Colman A. Lamin B1 fluctuations have differential effects on cellular proliferation and senescence. J Cell Biol. 2013 Mar 4;200(5):605-17. doi: 10.1083/jcb.201206121. Epub 2013 Feb 25. PubMed PMID: 23439683; PubMed Central PMCID: PMC3587829. Link
Zhao TY, Goh KJ, Ng HH and Vardy LA (2012). A role for polyamine regulators in ESC self-renewal. Cell Cycle. Volume 11, Issue 24 December 15, 2012.
Beillard E, Ong SC, Giannakakis A, Guccione E, Vardy LA, Voorhoeve PM. (2012) miR-Sens--A retroviral dual-luciferase reporter to detect microRNA activity in primary cells. RNA. 2012 Mar 14.
Zhang D, Zhao TY, Ang HS, Chong P, Saiki R, Igarashi k, Yang H, Vardy LA. (2012) Amd1 is essential for ES cell self-renewal and is translationally down regulated on differentiation to neural precursor cells. Genes and Development. March 1, 2012 26: 461-473.
Inaki K, Hillmer AM, Ukil L, Yao F, Woo XY, Vardy LA, Zawack KF, Lee CW, Ariyaratne PN, Chan YS, Desai KV, Bergh J, Hall P, Putti TC, Ong WL, Shahab A, Cacheux- Rataboul V, Karuturi RK, Sung WK, Ruan X, Bourque G, Ruan Y, Liu ET. Transcriptional consequences of genomic structural aberrations in breast cancer. Genome Res. 2011 May;21(5):676-87. Epub 2011 Apr 5.
Brown S, Teo A, Pauklin S, Hannan N, Cho CH, Lim B, Vardy L, Dunn NR, Trotter M, Pedersen R, Vallier L. 2011. Activin/Nodal signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors. Stem Cells 29(8):1176-85.
Wang H, Vardy LA, Tan CP, Loo JM, Guo K, Li J, Lim SG, Zhou J, Chng WJ, Ng SB, Li HX and Zeng Q. (2010) PCBP1 Suppresses the Translation of Metastasis-Associated PRL-3 Phosphatase. Cancer Cell. 2010 Jul 13;18(1):52-62.
Vardy L, Pesin JA, and Orr-Weaver TL. (2009) Regulation of Cyclin A protein in meiosis and early embryogenesis. Proc Natl Acad Sci. 2009 Feb 10;106(6):1838-43.
Vardy L, Orr-Weaver TL. (2007) Regulating translation of maternal messages: multiple repression mechanisms. Trends Cell Biol. Oct 26 2007.
Vardy L, Orr-Weaver TL. (2007) The Drosophila PNG kinase complex regulates the translation of cyclin B. Dev Cell. Jan; 12(1):157-66.
Tadros W, Goldman AL, Babak T, Menzies F, Vardy L, Orr-Weaver T, Hughes TR, Westwood JT, Smibert CA, Lipshitz HD. (2007) SMAUG is a major regulator of maternal mRNA destabilization in Drosophila and its translation is activated by the PAN GU kinase. Dev Cell. Jan;12(1):143-55.
Lee LA, Lee E, Anderson MA, Vardy L, Tahinci E, Ali SM, Kashevsky H, Benasutti M, Kirschner MW, Orr-Weaver TL. (2005) Drosophila genome-scale screen for PAN GU kinase substrates identifies Mat89Bb as a cell cycle regulator. Dev Cell. 2005 Mar;8(3):435-42.
Sato M, Vardy L, Angel Garcia M, Toda T. (2004) Interdependency of fission yeast Alp14/TOG and coiled coil protein Alp7 in microtubule localization and bipolar spindle formation. Mol Biol Cell. 2004 Apr;15(4).
Sato M, Koonrugsa N, Toda T, Vardy L, Tournier S, Millar JB (2003) Deletion of Mia1/Alp7 activates Mad2-dependent spindle assembly checkpoint in fission yeast. Nat Cell Biol. 2003 Sep;5(9):764-6.
Vardy L, Toda T. (2002) The gamma-tubulin complex provides a link between the metaphase checkpoint and cytokinesis. Genes Cells. 2002 Apr;7(4):365-73.
Fujita A,* Vardy L,* Garcia MA, Toda T. (2002) A fourth component of the Fission yeast gamma-tubulin complex, Alp16, is required for cytoplasmic microtubule integrity and becomes indispensable when gamma-tubulin function is compromised. Mol. Biol. Cell. 2002 Jul;13(7):2360-73. *Joint first authorship.
Garcia MA, Vardy L, Koonrugsa N, Toda T. (2001) Fission Yeast ch-TOG/XMAP215 homologue Alp14 connects mitotic spindles with the kinetochore and is a component of the Mad2-dependent spindle checkpoint. EMBO J. 2001. 20: 3389-3401.
Vardy L, Toda T. (2000) The fission yeast gamma-tubulin complex is required in G1 phase and is a component of the spindle assembly checkpoint. EMBO J. 2000.19. 6096-6111.
Radcliffe PA, Vardy L, Toda T. (2000) A conserved small GTP-binding protein Alp41 is essential for the cofactor-dependent biogenesis of microtubules in fission yeast. FEBS Lett. 2000. 468. 84-88.