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| Certification Type: |
Award, 1st John H. Walsh Research Prize, 2009, UCLA School of Medicine, Deans Office,
Professional Affiliation, UCLA ACCESS PhD Program Admission Committee
Professional Affiliation, UCLA MDPhD Program (MSTP) Admission Committee
Award, Young Investigator Award, CIRM, 2008
Award, Director’s New Innovator Award, National Institute of Health, 2007
Award, V Foundation Scholar, 2007
Award, Kimmel Foundation Scholar, 2007
Award, Junior Scientist Award of the States Berlin and Brandenburg, Germany, 2001
Award, Byk-Gulden Graduate Thesis Award of the German Society of Biochemistry, 2000
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| Degree: |
Ph.D., Cell Biology, 1999
M.S., Biochemistry, 1994
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| Academic Experience: |
Postdoctoral, Epigenetic control in ES cells, The Whitehead Institute, Cambridge, Massachusetts
Postdoctoral, Study of X-inactivation, University of California, San Francisco
Fellowship, Special Fellow of the Leukemia and Lymphoma Society, 2004
Fellowship, Life Sciences Research Foundation Postdoctoral Fellowship, 2001
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| Laboratory Address: |
BSRB 35410-14
UCLA School of Medicine
615 Charles E. Young Drive South
Los Angeles, CA 90095
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| Mailing Address: |
Mailing Address
Department of Biological Chemistry
UCLA School of Medicine
PO Box 951737
Los Angeles, CA 90095
UNITED STATES
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| Office Address: |
BSRB room 390D
UCLA School of Medicine
615 Charles E. Young Drive South
David Geffen School of Medicine, UCLA
Los Angeles, CA 90095
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Work Phone Number:
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(310) 206-8688
office
(310) 267-0087
lab
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Epigenetic regulation of stem cell self-renewal, differentiation, and cancer
The aim of our research is to understand how changes in chromatin structure are established and maintained in mammalian development to control gene expression, DNA replication, and cellular identity. We use embryonic stem (ES) cells as a model system to study most of these questions. ES cells have the amazing and unique ability to self-renew and differentiate into all cell types of the mammalian body. Currently, the work in our lab can broadly be divided into four areas.
1. We are studying the mechanism of how one of the two X chromosomes in female mammalian cells is transcriptionally silenced. X-inactivation is the most dramatic example of developmentally regulated heterochromatin formation in mammalian cells. The silencing of the X is initiated when embryonic stem cells differentiate, and cannot be induced in somatic cells. Questions are: How does the noncoding RNA Xist mediate silencing of the X chromosome? Why is initiation of silencing developmentally restricted? What is the developmental cue initiating X-inactivation? The inactive X is a fascinating process to study the relationship of noncoding RNAs, silencing of gene expression, and heterochromatin formation with an exciting link to embryonic stem cell differentiation. It is expected that understanding how the X is silenced will have wide implications for our understanding of developmentally regulated silencing of other regions in the genome.
2. We are attempting to understand how DNA replication, chromatin and transcriptional regulation are linked and how epigenetic information is inherited through cell division.
3. The development of the fertilized zygote into a complex organism has traditionally been viewed as a unidirectional process, with cells in the embryo becoming gradually 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 pluripotent embryonic state. This process has been termed nuclear reprogramming. We have recently been able to reprogram murine and human fibroblasts to an embryonic stem cell state directly by simply overexpressing four transcription factors in fibroblasts following a strategy first proposed by Shinya Yamanaka in 2006. An important goal is to understand the mechanism by which transcription factor- induced reprogramming occurs and to develop tools that improve the applicability of human iPS cells for clinical applications. Since the generation of iPS cells represents a manipulation that “plays the development tape backwards”, it provides a simple complementary approach with which to accelerate mechanistic dissection of the role of chromatin in cell fate switching, lineage commitment, stabilization of the differentiated state, and pluripotency.
4. The chromatin-regulatory processes we study are often deregulated in diseases. Importantly, many of the factors that we study are highly expressed in embryonic stem cells and cancer cells, while hardly detectable in somatic cells. Therefore, an extension of our work on epigenetic regulation of gene expression during development is to analyze the contribution of chromatin-based mechanisms to disease states, particularly prostate cancer.
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Kathrin Plath was born in Germany. She did her Graduate work with Dr. Tom Rapoport at Harvard Medical School. For her thesis, she defined how the signal sequence of a secretory protein is recognized by the translocation channel in the endoplasmic reticulum membrane. This was followed by post-doctoral work in the laboratory of Dr. Barbara Panning at the University of California, San Francisco, where she started to work on X-inactivation in female mammalian cells. In 2003, Kathrin moved to the laboratory of Dr. Rudolf Jaenisch at the Whitehead Institute at MIT to study the function of Polycomb Group Proteins in embryonic stem cells. Kathrin joined the Department of Biological Chemistry as an Assistant Professor in 2006.
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Gaspar-Maia Alexandre, Alajem Adi, Polesso Fanny, Sridharan Rupa, Mason Mike J, Heidersbach Amy, Ramalho-Santos João, McManus Michael T, Plath Kathrin, Meshorer Eran, Ramalho-Santos Miguel. Chd1 regulates open chromatin and pluripotency of embryonic stem cells.
Nature.
2009; 460(7257):
863-8.
Mason Mike J, Fan Guoping, Plath Kathrin, Zhou Qing, Horvath Steve. Signed weighted gene co-expression network analysis of transcriptional regulation in murine embryonic stem cells.
BMC Genomics.
2009; 10(7257):
327.
Chin Mark H, Mason Mike J, Xie Wei, Volinia Stefano, Singer Mike, Peterson Cory, Ambartsumyan Gayane, Aimiuwu Otaren, Richter Laura, Zhang Jin, Khvorostov Ivan, Ott Vanessa, Grunstein Michael, Lavon Neta, Benvenisty Nissim, Croce Carlo M, Clark Amander T, Baxter Tim, Pyle April D, Teitell Mike A, Pelegrini Matteo, Plath Kathrin, Lowry William E. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures.
Cell Stem Cell.
2009; 5(1):
111-23.
Park Tae Sub, Galic Zoran, Conway Anne E, Lindgren Anne, van Handel Benjamin J, Magnusson Mattias, Richter Laura, Teitell Michael A, Mikkola Hanna K A, Lowry William E, Plath Kathrin, Clark Amander T. Derivation of primordial germ cells from human embryonic and induced pluripotent stem cells is significantly improved by coculture with human fetal gonadal cells.
Stem Cells.
2009; 27(4):
783-95.
Karumbayaram Saravanan, Novitch Bennett G, Patterson Michaela, Umbach Joy A, Richter Laura, Lindgren Anne, Conway Anne E, Clark Amander T, Goldman Steve A, Plath Kathrin, Wiedau-Pazos Martina, Kornblum Harley I, Lowry William E. Directed differentiation of human-induced pluripotent stem cells generates active motor neurons.
Stem Cells.
2009; 27(4):
806-11.
Daley George Q, Lensch M William, Jaenisch Rudolf, Meissner Alex, Plath Kathrin, Yamanaka Shinya. Broader implications of defining standards for the pluripotency of iPSCs.
Cell Stem Cell.
2009; 4(3):
200-1.
Hochedlinger Konrad, Plath Kathrin. Epigenetic reprogramming and induced pluripotency.
Development.
2009; 136(4):
509-23.
Xie Wei, Song Chunying, Young Nicolas L, Sperling Adam S, Xu Feng, Sridharan Rupa, Conway Anne E, Garcia Benjamin A, Plath Kathrin, Clark Amander T, Grunstein Michael. Histone h3 lysine 56 acetylation is linked to the core transcriptional network in human embryonic stem cells.
Molecular Cell.
2009; 33(4):
417-27.
Saxe Jonathan P, Tomilin Alexey, Schöler Hans R, Plath Kathrin, Huang Jing. Post-translational regulation of Oct4 transcriptional activity.
PloS One.
2009; 4(2):
e4467.
Sridharan Rupa, Tchieu Jason, Mason Mike J, Yachechko Robin, Kuoy Edward, Horvath Steve, Zhou Qing, Plath Kathrin. Role of the murine reprogramming factors in the induction of pluripotency.
CELL.
2009; 136(2):
364-77.
Lowry William E and Plath Kathrin. The many ways to make an iPS cell.
Nature Biotechnology.
2008; 26(11):
1246-8.
Sridharan Rupa and Plath Kathrin. Illuminating the black box of reprogramming.
Cell Stem Cell.
2008; 2(4):
295-7.
Schenke-Layland Katja, Rhodes Katrin E, Angelis Ekaterini, Butylkova Yekaterina, Heydarkhan-Hagvall Sepideh, Gekas Christos, Zhang Rui, Goldhaber Joshua I, Mikkola Hanna K, Plath Kathrin, MacLellan W Robb Reprogrammed mouse fibroblasts differentiate into cells of the cardiovascular and hematopoietic lineages..
Stem Cells.
2008; 26(6):
1537-46.
Lowry W E, Richter L, Yachechko R, Pyle A D, Tchieu J, Sridharan R, Clark A T, Plath K Generation of human induced pluripotent stem cells from dermal fibroblasts..
Proc. Natl. Acad. Sci. U.S.A..
2008; 105(8):
2883-8.
Maherali, N.#, Sridharan, R.#, Xie, W., Utikal, J., Eminli, S., Arnold, K., Stadtfeld, M., Yachechko, R., Tchieu. J., Jaenisch, R., Plath, K.*, and Hochedlinger, K*. Directly Reprogrammed Fibroblasts Show Global Epigenetic Remodeling and Widespread Tissue Contribution.
Cell Stem Cell
2007; 1(1):
55-70 #equal contribution; * co-corresponding authors.
Nusinow Dmitri A, Sharp Judith A, Morris Alana, Salas Sonia, Plath Kathrin, Panning Barbara The histone domain of macroH2A1 contains several dispersed elements that are each sufficient to direct enrichment on the inactive X chromosome..
J. Mol. Biol..
2007; 371(1):
11-8.
Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES A bivalent chromatin structure marks key developmental genes in embryonic stem cells.
Cell.
2006; 125(2):
315-26.
Boyer LA*, Plath K*, Zeitlinger J, Brambrink T,
Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A,
Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jaenisch R Polycomb complexes repress developmental regulators in murine embryonic stem cells.
Nature.
2006; 441:
349-353 * both authors contributed equally.
Chu F, Nusinow DA, Chalkley RJ, Plath K, Panning B, Burlingame AL Mapping post-translational modifications of the histone variant MacroH2A1 using tandem mass spectrometry.
Mol Cell Proteomics.
2006; 5(1):
194-203.
Beard C, Hochedlinger K, Plath K, Wutz A, Jaenisch R Efficient method to generate single-copy transgenic mice by site-specific integration in embryonic stem cells.
Genesis.
2006; 44(1):
23-8.
de la Cruz CC, Fang J, Plath K, Worringer KA, Nusinow DA, Zhang Y, Panning B Developmental regulation of Suz 12 localization.
Chromosoma.
2005; 114(3):
183-92.
Plath K, Talbot D, Hamer KM, Otte AP, Yang TP, Jaenisch R, Panning B Developmentally regulated alterations in Polycomb repressive complex 1 proteins on the inactive X chromosome.
J Cell Biol.
2004; 167(6):
1025-35.
Plath K, Wilkinson BM, Stirling CJ, Rapoport TA Interactions between Sec complex and prepro-alpha-factor during posttranslational protein transport into the endoplasmic reticulum.
Mol Biol Cell.
2004; 15(1):
1-10.
Plath K*, Fang J*, Mlynarczyk-Evans SK, Cao R, Worringer KA, Wang H, de la Cruz CC, Otte AP, Panning B, Zhang Y Role of histone H3 lysine 27 methylation in X inactivation.
Science.
2003; 300(5616):
131-5 * both authors contributed equally.
Plath K, Mlynarczyk-Evans S, Nusinow DA, Panning B Xist RNA and the mechanism of X chromosome inactivation.
Annu Rev Genet.
2002; 36:
233-78.
Plath K, Rapoport TA Spontaneous release of cytosolic proteins from posttranslational substrates before their transport into the endoplasmic reticulum.
J Cell Biol.
2000; 151(1):
167-78.
Menetret JF, Neuhof A, Morgan DG, Plath K, Radermacher M, Rapoport TA, Akey CW The structure of ribosome-channel complexes engaged in protein translocation.
Mol Cell.
2000; 6(5):
1219-32.
Matlack KE, Misselwitz B, Plath K, Rapoport TA BiP acts as a molecular ratchet during posttranslational transport of prepro-alpha factor across the ER membrane.
Cell.
1999; 97(5):
553-64.
Rapoport TA, Matlack KE, Plath K, Misselwitz B, Staeck O Posttranslational protein translocation across the membrane of the endoplasmic reticulum.
Biol Chem.
1999; 380(10):
1143-50.
Plath K, Mothes W, Wilkinson BM, Stirling CJ, Rapoport TA Signal sequence recognition in posttranslational protein transport across the yeast ER membrane.
Cell.
1998; 94(6):
795-807.
Matlack KE, Plath K, Misselwitz B, Rapoport TA Protein transport by purified yeast Sec complex and Kar2p without membranes.
Science.
1997; 277(5328):
938-41.
Hanein D, Matlack KE, Jungnickel B, Plath K, Kalies KU, Miller KR, Rapoport TA, Akey CW Oligomeric rings of the Sec61p complex induced by ligands required for protein translocation.
Cell.
1996; 87(4):
721-32.
Finke K*, Plath K*, Panzner S, Prehn S, Rapoport TA, Hartmann E, Sommer T A second trimeric complex containing homologs of the Sec61p complex functions in protein transport across the ER membrane of S. cerevisiae.
Embo J.
1996; 15(7):
1482-94 * both authors contributed equally.
Engel K, Schultz H, Martin F, Kotlyarov A, Plath K, Hahn M, Heinemann U, Gaestel M Constitutive activation of mitogen-activated protein kinase-activated protein kinase 2 by mutation of phosphorylation sites and an A-helix motif.
J Biol Chem.
1995; 270(45):
27213-21.
Plath K, Engel K, Schwedersky G, Gaestel M Characterization of the proline-rich region of mouse MAPKAP kinase 2: influence on catalytic properties and binding to the c-abl SH3 domain in vitro.
Biochem Biophys Res Commun.
1994; 203(2):
1188-94.
Engel K, Plath K, Gaestel M The MAP kinase-activated protein kinase 2 contains a proline-rich SH3-binding domain.
FEBS Lett.
1993; 336(1):
143-7.
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