Randy Jirtle

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Randy L. Jirtle
Randy Jirtle.jpg
Born (1947-11-09)November 9, 1947
Kewaunee, Wisconsin, USA
Residence Durham, North Carolina, USA
Fields Epigenetics, Genomic imprinting, Radiation biology
Institutions Duke University, University of Wisconsin-Madison, University of Bedfordshire, North Carolina State University
Alma mater University of Wisconsin-Madison
Known for Evolution of genomic imprinting and identifying imprinted genes. Showing that environmental agents alter the epigenome, thereby affecting health and disease susceptibility in adulthood.
Website
randyjirtle.com

Randy Jirtle (born 9 November 1947) is an American biologist noted for his pioneering research in epigenetics, the branch of biology that deals with inherited information that does not reside in the nucleotide sequence of DNA.[1] Recently retired from Duke University, Durham, North Carolina, Jirtle is currently Visiting Professor at the McArdle Laboratory of Cancer Research, University of Wisconsin, Madison, WI and Professor of Epigenetics at the Department of Sport and Exercise Sciences, University of Bedfordshire, Bedford, UK.[2] Jirtle is noted for his research on genomic imprinting, and for his use of the Agouti mouse model to investigate the effect of environmental agents on the mammalian epigenome and disease susceptibility.

Early life and career[edit]

Jirtle was born in Kewaunee, Wisconsin. He attended Algoma Public High School and the University of Wisconsin-Madison, graduating with a B.S. degree in Nuclear Engineering. For graduate school, he remained at the University of Wisconsin-Madison, obtaining an M.S. in Radiation Biology in 1973 and a PhD in 1976 (Major: Radiation Biology; Minor: Statistics). Following post-doctoral studies, Jirtle was appointed Assistant Professor of Radiology at Duke University in 1980, and became Professor of Radiation Oncology in 1990 and Associate Professor of Pathology in 1998. He remained at Duke until 2012, and is currently a Senior Scientist at the McArdle Laboratory of Cancer Research, University of Wisconsin in Madison, WI, and Professor of Epigenetics at the Department of Sport and Exercise Sciences, University of Bedfordshire, Bedford, UK, and an Adjunct Professor of Epigenetics in the Department of Biological Sciences at North Carolina State University, Raleigh, NC.[3]

Research[edit]

Jirtle has long been interested in how environmental agents influence biological systems. His early research examined the influence of radiation on biological systems. He developed the first in vivo clonogenic assay for hepatocytes,[4] and used it to quantify their survival when exposed to X-rays[5][6] and neutrons.[7] Jirtle also used this clonal assay to study the phenomenon of liver regeneration,[8] and published a book on liver regeneration and carcinogenesis in 1995.[9] These early studies ultimately led to the identification of the insulin-like growth factor receptor (IGF2R) as a human tumor suppressor gene,[10][11] and to studies in the emerging field of genomic imprinting, since murine IGF2R was shown at that time to be imprinted.[12]

Genomic imprinting is an example of epigenetic inheritance that results in the maternal and paternal copies of certain genes being expressed differently. The evolutionary origin of genomic imprinting has been hotly debated, and the conflict theory was proposed to explain its development.[13] This theory posits that imprinting evolved in response to a genetic ‘battle between the sexes’ to determine the level of maternal resources invested in each offspring. Jirtle examined the imprint status of the IGF2R and IGF2 in what, at the time, were unconventional species (opossum and platypus). The data generated from these phylogenetically informative species are consistent with the evolution of imprinting about 150 million years ago in a common ancestor to Therian mammals (i.e. Metatherians and Eutherians) with the advent of placentation and live birth without the use of a shelled egg,[14][15][16] and provide strong support for the conflict theory of imprinting evolution. Imprinted genes have been implicated in complex human disorders such as Alzheimer disease, autism, obesity, diabetes and schizophrenia. Jirtle has contributed to the better understanding of these human conditions by identifying novel imprinted genes, either by biochemical analysis of individual genes[17][18][19][20][21] or by genome-wide studies that used machine learning-based approaches to predict candidate imprinted genes, followed by biochemical examination of these candidates.[22][23]

The Developmental Origins of Health and Disease (DOHaD) hypothesis proposes that early life experiences can be captured and retained into adulthood, thus influencing the development of adult disease. Jirtle’s most influential scientific accomplishment is a series of papers in which his use of the Agouti mouse experimental system demonstrates that the ‘memory system’ for this phenomenon involves epigenetic modifications.

Isogenic Avy mice of the same age and sex. Coat color and obesity depend upon the epigenetic status of the Avy allele

In 2003, he provided convincing molecular evidence that maternal dietary supplementation of Agouti viable yellow (Avy) mice with methyl donors (i.e. folic acid, choline, vitamin B12, and betaine) altered the coat color distribution and disease susceptibility in genetically identical offspring by increasing DNA methylation at the Avy locus.[24] This paper is classified as a ‘Highly Cited Paper’ in Essential Science Indicators from Thomson Reuters, and was one of the key papers in ScienceWatch’s Special Topics Research Front Map on Epigenetic Gene Regulation (2009). A subsequent study[25] showed that the phyto-estrogen, genistein, modifies the fetal epigenome, alters coat color, and protects Agouti offspring from obesity even though it is not capable of donating a methyl group. This article was selected as the ‘Classic Paper of the Year’ in 2011 by Environmental Health Perspectives.[26] It was followed by a study that showed that genistein and methyl donor supplementation can counteract detrimental epigenetic effects induced by a controversial xenobiotic chemical, bisphenol A (BPA).[27] Returning to his radiation biology training, Jirtle recently used the Avy mouse system to show that embryonic stem cells exposed in vivo to low doses of a physical agent, X-rays, induce positive adaptive responses in the offspring by altering the epigenome, and that these changes are mitigated by antioxidants.[28][29] Together these studies were instrumental in ushering in the era of environmental epigenomics by demonstrating that low levels of both chemical and physical agents can alter disease susceptibility in adulthood by modifying the epigenome.

Awards and Leadership[edit]

Jirtle has published many peer-reviewed manuscripts in the field of epigenetics. He has been an invited speaker at numerous national and international meetings, and has presented a number of named lectureships. He has organized several international scientific meetings including, in 2005, a seminal conference entitled ‘Environmental epigenomics, imprinting and disease susceptibility’ and, in 2011, a Keystone Meeting entitled ‘Environmental Epigenomics and Disease Susceptibility’. His research on the Agouti mouse system was prominently featured in the PBS NOVA program ‘Ghost in Your Genes’, originally broadcast in 2007. Jirtle presented the NIH Director’s WALS lecture in 2012 entitled Epigenetics: How Genes and Environment Interact. In 2013, he participated in the epigenetic session Destiny and DNA: Our Pliable Genome at the World Science Festival in New York City. He has edited a book on Liver Regeneration and Carcinogenesis,[9] and two books on Environmental Epigenomics in Health and Disease.[30][31] Dr. Jirtle received the Linus Pauling Award from the Institute of Functional Medicine in 2014.

In 2007 Jirtle was nominated to be Time Magazine’s Person of the Year by Dr. Nora Volkow, Director of the National Institute on Drug Abuse. In her nomination, she stated “I’d select the Duke University scientist whose pioneering work in epigenetics and genomic imprinting has uncovered a vast territory in which a gene represents less of an inexorable sentence and more of an access point for the environment to modify the genome. The trailblazing discoveries of Dr. Jirtle have produced a far more complete and useful understanding of human development and diseases”.[32]

References[edit]

  1. ^ Allis, CD, Jenuwein T, Reinberg D, Caparros, M-L (eds.) (2007), Epigenetics, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press, ISBN 0879698756
  2. ^ http://www.randyjirtle.com/research
  3. ^ http://www.randyjirtle.com/Jirtle-CV.pdf
  4. ^ Jirtle RL, Biles C, Michalopoulos G (1980), "Morphologic and histochemical analysis of hepatocytes transplanted into syngeneic hosts", Am J Pathol 101: 115–126. PMID 6108719
  5. ^ Jirtle RL, Michalopoulos G, McLain JR, Crowley J (1981), "Transplantation system for determining the clonogenic survival of parenchymal hepatocytes exposed to ionizing radiation", Cancer Res 41: 3512–3518. PMID 7020930
  6. ^ Jirtle RL, McLain JR, Strom SC, Michalopoulos G (1982), "Repair of radiation damage in noncycling parenchymal hepatocytes", Br J Radiol 55: 847–851. PMID 6753999
  7. ^ Jirtle RL, Michalopoulos G, Strom SC, DeLuca PM, Gould MN (1984), "The survival of parenchymal hepatocytes irradiated with low and high LET radiation", Br J Cancer Suppl 6: 197–201. PMID 6692410
  8. ^ Jirtle RL, Michalopoulos G (1982), "Effects of partial hepatectomy on transplanted hepatocytes", Cancer Res. 42: 3000–3004. PMID 7046913
  9. ^ a b Jirtle, RL, ed. (1995), Liver Regeneration and Carcinogenesis: Cellular and Molecular Mechanisms, San Diego: Academic Press, ISBN 012388649X 
  10. ^ De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL (1995), "M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity", Nat Genet 11: 447–449. PMID 7493029
  11. ^ Hankins GR, De Souza AT, Bentley RC, Patel MR, Marks JR, Iglehart JD, Jirtle RL (1996), "M6P/IGF2 receptor: a candidate breast tumor suppressor gene", Oncogene 12: 2003–2009. PMID 8649861
  12. ^ Barlow DP, Stoger R, Herrmann BG, Saito K, Schweifer N (1991), "The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus", Nature 349: 84–87. PMID 1845916
  13. ^ Moore T, Haig D (1991), "Genomic imprinting in mammalian development: a parental tug-of-war", Trends Genet 7: 45–49. PMID 2035190
  14. ^ Killian JK, Byrd JC, Jirtle JV, Munday BL, Stoskopf MK, MacDonald RG, Jirtle RL (2000), "M6p/igf2r imprinting evolution in mammals", Mol Cell 5: 707–716. PMID 10882106
  15. ^ Killian JK, Nolan CM, Stewart N, Munday BL, Andersen NA, Nicol S, Jirtle RL (2001), "Monotreme IGF2 expression and ancestral origin of genomic imprinting", J Exp Zool 291: 205–212. PMID 11479919
  16. ^ Nolan CM, Killian JK, Petitte JN, Jirtle RL (2001), "Imprint status of M6P/IGF2R and IGF2 in chickens", Dev Genes Evol 211: 179–183. PMID 11455432
  17. ^ Wylie AA, Murphy SK, Orton TC, Jirtle RL (2000), "Novel imprinted DLK1/GTL2 domain on human chromosome 14 contains motifs that mimic those implicated in IGF2/H19 regulation", Genome Res 10: 1711–1718. PMID 11076856
  18. ^ Evans HK, Wylie AA, Murphy SK, Jirtle RL (2001), "The neuronatin gene resides in a 'micro-imprinted' domain on human chromosome 20q11.2", Genomics 77: 99–104. PMID 11543638
  19. ^ Murphy SK, Wylie AA, Jirtle RL (2001), "Imprinting of PEG3, the human homologue of a mouse gene involved in nurturing behavior", Genomics 71: 110–117. PMID 11161803
  20. ^ Zhang A, Skaar DA, Li Y, Huang D, Price TM, Murphy SK, Jirtle RL (2011), "Novel retrotransposed imprinted locus identified at human 6p25", Nucleic Acids Res 39: 5388–5400. PMID 21421564
  21. ^ Das R, Anderson N, Koran MI, Weidman JR, Mikkelsen TS, Kamal M, Murphy SK, Linblad-Toh K, Greally JM, Jirtle RL (2012), "Convergent and divergent evolution of genomic imprinting in the marsupial Monodelphis domestica", BMC Genomics 13: 394. PMID 22899817
  22. ^ Luedi PP, Hartemink AJ, Jirtle RL (2005), "Genome-wide prediction of imprinted murine genes", Genome Res 15: 875–884. PMID 15930497
  23. ^ Luedi PP, Dietrich FS, Weidman JR, Bosko JM, Jirtle RL, Hartemink AJ (2007), "Computational and experimental identification of novel human imprinted genes", Genome Res 17: 1723–1730. PMID 18055845
  24. ^ Waterland RA, Jirtle RL (2003), "Transposable elements: targets for early nutritional effects on epigenetic gene regulation", Mol Cell Biol 23: 5293–5300. PMID 12861015
  25. ^ Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL (2006), "Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome", Environ Health Perspect 114: 567–572. PMID 16581547
  26. ^ Tilson HA (2011), "EHP Classic Paper of the Year, 2011", Environ Health Perspect 119: A238. PMID 21628120
  27. ^ Dolinoy DC, Huang D, Jirtle RL (2007), "Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development", PNAS 104: 13056–13061. PMID 17670942
  28. ^ Bernal AJ, Dolinoy DC, Huang D, Skaar DA, Weinhouse C, Jirtle RL (2013), "Adaptive radiation-induced epigenetic alterations mitigated by antioxidants", FASEB J 27: 665–671. PMID 23118028
  29. ^ "Low Dose Radiation-Induced Epigenetic Alterations Found in Agouti Mouse Model". US Department of Energy. 2007-11-08. Retrieved 2013-05-23. 
  30. ^ Jirtle, RL; Tyson, FL, eds. (2013), Environmental Epigenomics in Health and Disease: Epigenetics and Disease Origins, Heidelberg: Springer, ISBN 3642233791 
  31. ^ Jirtle, RL; Tyson, FL, eds. (2013), Environmental Epigenomics in Health and Disease: Epigeneitcs and Complex Diseases Origins, Heidelberg: Springer, ISBN 3642368263 
  32. ^ "Person of the Year 2007". Time Magazine. 2007-11-08. Retrieved 2013-05-23. 

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