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Kevin Eggan:Using Cloning to Study Degenerative Diseases PDF Print E-mail
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Wednesday, 15 June 2011 16:16
While earning his PhD, Kevin Eggan helped make Rudolf Jaenischs lab at the Whitehead Institute for Biomedical Research a preeminent cloning lab. Eggan became "arguably the most skillful mouse cloner in this country," says Jaenisch. Eggan used those skills to clone mice from neurons, proving that animals could be cloned from even the most specialized cells in the body -- a feat that many scientists considered impossible. Eggan also helped explain how cloning "reprograms" the genetic material from an adult mouse cell, identifying the changes that take place to reset the nucleus to the beginning of development.

Eggan, now an assistant professor of molecular and cellular biology, plans to create human stem cell lines from patients with neurodegenerative disorders such as Parkinsons and Lou Gehrigs diseases, in order to study disease development and search for new drugs. He has also begun studying nuclear reprogramming in human cells in the hope of finding a way to create patient-specific embryonic stem cells without using human eggs.

Research Summary:

The genome is not merely a passive repository of genetic information.  Chromosomes are dynamic entities undergoing structural changes that underlie development and cellular differentiation. We are interested in how developmental and environmental cues induce heritable variation in chromatin structure and how these variations regulate developmental potency, cell-fate and gene expression.

The development of the fertilized zygote into a complex organism has traditionally been understood as a unidirectional process, with cells in the embryo becoming gradually more committed to a specific tissue type.  However, nuclear transfer experiments have demonstrated that the mammalian egg can relieve the constraints imposed by cellular differentiation and return the nucleus of an adult cell to a totipotent embryonic state.  This process has been termed nuclear reprogramming.  The primary research focus of our group is to understand the mechanisms by which reprogramming occurs.  In particular, we wish to determine the nature of epigenetic information that is reprogrammed (i.e., aspects of DNA methylation and chromatin structure), the times at which reprogramming events occur and the identities of the molecular machinery that accomplish reprogramming. 

In addition, we are using nuclear transfer and other approaches to develop human embryonic stem cell lines that carry the genes responsible for human neurodegenerative disease.  It is our hope that these cell lines will provide valuable model systems for the in vitro study of these diseases.

Publications:

Deng J, Shoemaker R, Xie B, Gore A, LeProust EM, Antosiewicz-Bourget J, Egli D, Maherali N, Park IH, Daley GQ, Eggan K, Hochedlinger K, Thomson J, Wang W, Gao Y, Zhang K. Targeted bisulfite sequencing reveals changes in DNA methylation association with nuclear reprogramming. Nat Biotechnol. 2009 Aprl; 27(4): 353-60. Epub 2009 Mar 29.

Chen AE, Egli D, Niakan K, Deng J, Akutsu H, Yamaki M, Cowan C, Fitz-Gerald C, Zhang K, Melton DA, Eggan K. Optimal timing of inner cell mass isolation increases the efficiency of human embryonic stem cell derivation and allows generation of sibling cell lines. Cell Stem Cell. 2009 Feb 6; 4(2):103-6.

Di Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC. Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell. 2008 Dec 4; 3(6): 637-48.

Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R, Wichterle H, Henderson CE, Eggan K. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science. 2008 Aug 29; 321(5893):1218-21. Epub 2008 Jul 31.

Sullivan S, Egli D, Akutsu H, Melton DA, Eggan K, Cowan CA. Derivation of human ES cell lines, Human Embryonic Stem Cells: The pratical handbook. John Wiley & Sons, Ltd., Chinchester, June 2007. Hardback 434 pages. ISBN: 978-0-470-03356-2

Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci. 2007 May;10(5):608-614. Epub 2007 Apr 15.

Eggan K. Dolly's legacy: human nuclear transplantation and better medicines for our children. Cloning Stem Cells. 2007 Spring;9(1):21-5.

Rodolfa KT, Eggan K. A transcriptional logic for nuclear reprogramming. Cell. 2006 Aug 25;126(4):652-5.

Eggan K, Jurga S, Gosden R, Min IM, Wagers AJ. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature. 2006 Jun 29;441(7097):1109-14.

Cowan CA, Atienza J, Melton DA, Eggan K. Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science. 2005 Aug 26;309(5739):1369-73. Affymetrix Data

Jaenisch R, Hochedlinger K, Eggan K. Nuclear cloning, epigenetic reprogramming and cellular differentiation. Novartis Found Symp. 2005;265:107-18; discussion 118-28.

Jaenisch R, Hochedlinger K, Blelloch R, Yamada Y, Baldwin K, Eggan K. Nuclear cloning, epigenetic reprogramming, and cellular differentiation. Cold Spring Harb Symp Quant Biol. 2004;69:19-27.

Eggan K, Baldwin K, Tackett M, Osborne J, Gogos J, Chess A, Axel R, Jaenisch R.  Mice cloned from olfactory sensory neurons. Nature. 2004 Mar 4;428(6978):44-9.

Geijsen N, Horoschak M, Kim K, Gribnau J, Eggan K, Daley GQ. Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature. 2004 Jan 8;427(6970):148-54.

Eggan K, Jaenisch R. Differentiation of F1 embryonic stem cells into viable male and female mice by tetraploid embryo complementation. Methods Enzymol. 2003;365:25-39.

Eggan K, Jaenisch R. Micromanipulating dosage compensation: understanding X-chromosome inactivation through nuclear transplantation. Semin Cell Dev Biol. 2003 Dec;14(6):349-58.

Bortvin A, Eggan K, Skaletsky H, Akutsu H, Berry DL, Yanagimachi R, Page DC, Jaenisch R. Incomplete reactivation of Oct4-related genes in mouse embryos cloned from somatic nuclei. Development. 2003 Apr;130(8):1673-80.

Jaenisch R, Eggan K, Humpherys D, Rideout W, Hochedlinger K. Nuclear cloning, stem cells, and genomic reprogramming. Cloning Stem Cells. 2002;4(4):389-96.

Humpherys D, Eggan K, Akutsu H, Friedman A, Hochedlinger K, Yanagimachi R, Lander ES, Golub TR, Jaenisch R. Abnormal gene expression in cloned mice derived from embryonic stem cell and cumulus cell nuclei. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12889-94..

Eggan K, Rode A, Jentsch I, Samuel C, Hennek T, Tintrup H, Zevnik B, Erwin J, Loring J, Jackson-Grusby L, Speicher MR, Kuehn R, Jaenisch R. Male and female mice derived from the same embryonic stem cell clone by tetraploid embryo complementation. Nat Biotechnol. 2002 May;20(5):455-9.

Biniszkiewicz D, Gribnau J, Ramsahoye B, Gaudet F, Eggan K, Humpherys D, Mastrangelo MA, Jun Z, Walter J, Jaenisch R. Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mol Cell Biol. 2002 Apr;22(7):2124-35.

Possemato R, Eggan K, Moeller BJ, Jaenisch R, Jackson-Grusby L. Flp recombinase regulated lacZ expression at the ROSA26 locus. Genesis. 2002 Feb;32(2):184-6.

Rideout WM 3rd, Eggan K, Jaenisch R. Nuclear cloning and epigenetic reprogramming of the genome. Science. 2001 Aug 10;293(5532):1093-8.

Humpherys D, Eggan K, Akutsu H, Hochedlinger K, Rideout WM 3rd, Biniszkiewicz D, Yanagimachi R, Jaenisch R. Epigenetic instability in ES cells and cloned mice. Science. 2001 Jul 6;293(5527):95-7.

Eggan K, Akutsu H, Loring J, Jackson-Grusby L, Klemm M, Rideout WM 3rd, Yanagimachi R, Jaenisch R. Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6209-14.

Eggan K, Akutsu H, Hochedlinger K, Rideout W 3rd, Yanagimachi R, Jaenisch R. X-Chromosome inactivation in cloned mouse embryos. Science. 2000 Nov 24;290(5496):1578-81.

Rideout WM 3rd, Wakayama T, Wutz A, Eggan K, Jackson-Grusby L, Dausman J, Yanagimachi R, Jaenisch R. Generation of mice from wild-type and targeted ES cells by nuclear cloning. Nat Genet. 2000 Feb;24(2):109-10.

 
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