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Thomas Jenuwein

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Thomas Jenuwein
April 2019
Born (1956-12-10) 10 December 1956 (age 67)
Lohr am Main, Germany
NationalityGerman
Alma materEMBL, Heidelberg
Scientific career
FieldsEpigenetics
InstitutionsUCSF,
Research Institute of Molecular Pathology,
Max Planck Institute of Immunobiology and Epigenetics
Websitewww.ie-freiburg.mpg.de/jenuwein

Thomas Jenuwein (born 1956) is a German scientist working in the fields of epigenetics, chromatin biology, gene regulation and genome function.

Biography

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Thomas Jenuwein received his Ph.D. in molecular biology in 1987 from the EMBL, working on fos oncogenes in the laboratory of Rolf Müller[1] and the University of Heidelberg and performed postdoctoral studies (1987-1993) on the immunoglobulin heavy chain (IgH) enhancer with Rudolf Grosschedl[2] at the University of California San Francisco (UCSF). As an independent group leader (1993-2002) and then as a senior scientist (2002-2008) at the Research Institute of Molecular Pathology (IMP) in Vienna,[3] he focused his research to chromatin regulation. Through this work, he and his team discovered the first histone lysine methyltransferase (KMT) that was published in 2000.[4] He is currently director at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany where he heads the Department of Epigenetics.[5] From 2004 to 2009, he coordinated the EU-funded network of excellence 'The Epigenome'[6] , which connected more than 80 laboratories in Europe. Jenuwein is also co-editor of the first textbook on 'Epigenetics'[7] that was published by Cold Spring Harbor Laboratory Press in 2007 and 2015. He is an ambassador for the dissemination of Science and is actively engaged with public lectures[8][9] and radio and TV documentations[10][11] to inform lay audiences about 'Epigenetics'.

Career and research

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Chromatin is the physiological template of our genetic information, the DNA double helix. The basic subunits of chromatin, the histone proteins, function in the packaging of the DNA double helix and in controlling gene expression through a variety of histone modifications. When Jenuwein started his chromatin work in late 1993, no enzymes for histone modifications were known. He and his team cloned and characterized mammalian orthologs of dominant Drosophila PEV modifier factors containing the evolutionarily conserved SET domain,[12][13] originally identified by the laboratory of Gunter Reuter.[14] The SET domain is present in Su(var)3–9, Enhancer of zeste and Trithorax proteins, all of which had been implicated in epigenetic regulation without evidence of enzymatic activity. Overexpression of human SUV39H1 modulated the distribution of histone H3 phosphorylation during the cell cycle in a SET domain dependent manner.[15] This insight, together with refined bioinformatic interrogation revealing a distant relationship of the SET domain with plant methyltransferases, suggested the critical experiment: to test recombinant SUV39H1 for KMT activity on histone substrates. This experiment revealed robust catalytic activity of the SET domain of recombinant SUV39H1 to methylate histone H3 in vitro[4] and was shown to be selective for the histone H3 lysine 9 position (H3K9me3). This seminal discovery identified the first histone lysine methyltransferase for eukaryotic chromatin.[4][16][17] An important follow-up discovery was to show that SUV39H1-mediated H3K9 methylation generates a binding site for the chromodomain of heterochromatin protein 1 (HP1).[18] Together, these landmark findings established a biochemical pathway for the definition of heterochromatin and characterized Suv39h-dependent H3K9me3 as a central epigenetic modification for the repression of transcriptional activity. The in vivo function of the Suv39h KMT was demonstrated by the analysis of Suv39h double-null mice, which display chromosome segregation defects and develop leukemia.[19] Together with Boehringer Ingelheim, he identified the first small molecule inhibitor for KMT enzymes via screening of a chemical library.[20] During the following years, Jenuwein then addressed the function of heterochromatin towards transcriptional regulation and genomic organization, with a particular focus on the analysis of the non-coding genome. An initial map of the mouse epigenome was established by a cluster analysis of repressive histone modifications across repeat sequences[21] and provided an important framework well ahead of the deep-sequencing advances in the profiling of epigenomes. Genome-wide maps for Suv39h-dependent H3K9me3 marks and Hiseq RNA sequencing revealed a novel role for the Suv39h KMT in the silencing of repeat elements (e.g. LINE and ERV retrotransposons) in mouse embryonic stem cells.[22] The demonstration that the pericentric major satellite repeats have embedded transcription factor (TF) binding sites that are relevant for TF-mediated recruitment of Suv39h enzymes has provided a general targeting mechanism for the formation of heterochromatin.[23] Most recent work has identified that repeat RNA transcripts from the major satellite repeats largely remain chromatin associated and form an RNA-nucleosome scaffold that is supported by RNA:DNA hybrids.[24]

Significance and impact

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The impact of the discovery of the first KMT and its associated functions has been so broad that it stimulated novel lines of research spanning nearly all aspects of chromatin biology and epigenetic control for both basic and applied questions.[25] The definition of heterochromatin by the SUV39H1-H3K9me3-HP1 system has proven to be valid across nearly all model organisms.[26] It allowed the functional dissection between histone and DNA methylation and integrated the RNAi silencing pathway with H3K9 methylation.[7] Histone lysine methylation has opened molecular insights for the organization of the inactive X chromosome, telomeres and the rDNA cluster and is a crucial mechanism for Polycomb- and Trithorax-mediated gene regulation.[7] Histone lysine methylation marks also defined bivalent chromatin in embryonic stem cells and are instructive chromatin modifications that are used for epigenomic profiling in normal vs. diseased cells.[7] They were also a crucial prerequisite for the later discoveries of histone demethylases (KDM).[27] With all of these mechanistic insights, novel approaches in cancer biology, complex human disorders, cell senescence and reprogramming have become possible. Since histone lysine methylation marks (as well as the other histone modifications) are reversible, their enzymatic systems represent ideal targets for novel drug discovery programs that have greatly advanced epigenetic therapy. The response of chromatin to environmental signals and its possible epigenetic inheritance via the germ line is most likely also regulated, at least in part, by histone lysine methylation.

Honors and awards

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Jenuwein is a member of several learned societies, such as the European Molecular Biology Organization, Academia Europaea, the Austrian Academy of Sciences and the American Academy of Arts and Sciences. He was awarded an Honorary Professorship at the University of Vienna (2003) and a co-opting professorship with appointment at the Medical Faculty of the University of Freiburg (2010). In 2005, he obtained the Sir Hans Krebs Medal of the FEBS Society and in 2007 the Erwin Schrödinger Prize of the Austrian Academy of Sciences.

References

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  1. ^ Jenuwein T, Müller R (1987). "Structure-function analysis of fos protein: a single amino acid change activates the immortalizing potential of v-fos". Cell. 48 (4): 647–657. doi:10.1016/0092-8674(87)90243-1. PMID 3028645. S2CID 11189628.
  2. ^ Jenuwein T, Forrester WC, Qiu RG, Grosschedl R (1993). "The immunoglobulin μ enhancer core establishes factor access in nuclear chromatin independent of transcriptional stimulation". Genes & Development. 7 (10): 2016–2031. doi:10.1101/gad.7.10.2016. PMID 8406005.
  3. ^ "Thomas Jenuwein | Research Institute of Molecular Pathology".
  4. ^ a b c Rea S, Eisenhaber F, O'Carroll D, Strahl B, Sun ZW, Schmid M, Opravil S, Mechtler M, Ponting CP, Allis CD, Jenuwein T (2000). "Regulation of chromatin structure by site-specific histone H3 methyltransferases". Nature. 406 (6796): 593–599. Bibcode:2000Natur.406..593R. doi:10.1038/35020506. PMID 10949293. S2CID 205008015.
  5. ^ "Home". www.ie-freiburg.mpg.de.
  6. ^ "Epigenome NoE - Epigenome Network of Excellence".
  7. ^ a b c d "Epigenetics, Second Edition". cshlpress.com.
  8. ^ [1]. HSTalks.
  9. ^ [2]. www.mpg.de.
  10. ^ "Media Library". www.ie-freiburg.mpg.de.
  11. ^ "Wie die Zelle unsere Gene steuert". WDR Nachrichten. 1 July 2016.
  12. ^ Laible G, Wolf A, Nislow L, Pillus L, Dorn R, Reuter G, Lebersorger A, Jenuwein T (1997). "Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S.cerevisiae telomeres". The EMBO Journal. 16 (11): 3219–3232. doi:10.1093/emboj/16.11.3219. PMC 1169939. PMID 9214638.
  13. ^ Aagaard L, Laible G, Selenko P, Schmid M, Dorn R, Schotta G, Kuhfittig S, Wolf A, Lebersorger A, Singh PB, Reuter G, Jenuwein T (1999). "Functional mammalian homologues of the Drosophila PEV modifier Su(var)3–9 encode centromere-associated proteins which complex with the heterochromatin component M31". The EMBO Journal. 18 (7): 1923–1938. doi:10.1093/emboj/18.7.1923. PMC 1171278. PMID 10202156.
  14. ^ Tschiersch B, Hofmann A, Krauss V, Dorn R, Korge G, Reuter G (1994). "The protein encoded by the Drosophila position-effect variegation suppressor gene Su(var)3–9 combines domains of antagonistic regulators of homeotic gene complexes". The EMBO Journal. 13 (16): 3822–3831. doi:10.1002/j.1460-2075.1994.tb06693.x. PMC 395295. PMID 7915232.
  15. ^ Melcher M, Schmid M, Aagaard L, Selenko P, Laible G, Jenuwein T (2000). "Structure-function analysis of SUV39H1 reveals a dominant role in heterochromatin organisation, chromosome segregation and mitotic progression". Molecular and Cellular Biology. 20 (10): 3728–3741. doi:10.1128/mcb.20.10.3728-3741.2000. PMC 85674. PMID 10779362.
  16. ^ Jenuwein T (2006). "The epigenetic magic of histone lysine methylation". FEBS Journal. 273 (14): 3121–3135. doi:10.1111/j.1742-4658.2006.05343.x. PMID 16857008.
  17. ^ Pathology, Research Institute of Molecular. "Alumni Stories | Testimonials | Research Institute of Molecular Pathology (IMP)". The Research Institute of Molecular Pathology.
  18. ^ Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T (2001). "Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins". Nature. 410 (6824): 116–120. Bibcode:2001Natur.410..116L. doi:10.1038/35065132. PMID 11242053. S2CID 4331863.
  19. ^ Peters AH, O'Caroll D, Scherthan H, Mechtler K, Sauer S, Schöfer C, Weipoltshammer C, Pagani M, Lachner M, Kohlmaier A, Opravil S, Doyle M, Sibilia M, Jenuwein T (2001). "Loss of the Suv39h histone methyltrans-ferases impairs mammalian heterochromatin and genome stability". Cell. 107 (3): 323–337. doi:10.1016/s0092-8674(01)00542-6. PMID 11701123. S2CID 6712563.
  20. ^ Kubicek S, O'Sullivan RJ, August EM, Hickey ER, Zhang Q, Teodoro ML, Rea S, Mechtler K, Kowalski JR, Hamon CA, Kelly TA, Jenuwein T (2007). "Reversal of H3K9me2 by a small molecule inhibitor for the G9a histone methyltransferase". Molecular Cell. 25 (3): 473–481. doi:10.1016/j.molcel.2007.01.017. PMID 17289593.
  21. ^ Martens JH, O'Sullivan R, Braunschweig U, Opravil S, Radolf M, Steinlein P, Jenuwein T (2005). "The profile of repeat-associated histone lysine methylation states in the mouse epigenome". The EMBO Journal. 24 (4): 800–812. doi:10.1038/sj.emboj.7600545. PMC 549616. PMID 15678104.
  22. ^ Bulut-Karslioglu A, De La Rosa-Velázquez IA, Ramirez F, Barenboim M, Onishi-Seebacher M, Arand J, Galán C, Winter GE, Engist B, Gerle B, O'Sullivan RJ, Martens JH, Walter J, Manke T, Lachner M, Jenuwein T (2014). "Suv39h-dependent H3K9me3 marks intact retrotransposons and silences LINE elements in mouse embryonic stem cells". Molecular Cell. 55 (2): 277–290. doi:10.1016/j.molcel.2014.05.029. PMID 24981170.
  23. ^ Bulut-Karslioglu A, Perrera V, Scaranaro M, de la Rosa-Velazquez IA, van de Nobelen S, Shukeir N, Popow J, Gerle B, Opravil S, Pagani M, Meidhof S, Brabletz T, Manke T, Lachner M, Jenuwein T (2012). "A transcription factor-based mechanism for mouse heterochromatin formation". Nature Structural & Molecular Biology. 19 (10): 1023–1030. doi:10.1038/nsmb.2382. PMID 22983563. S2CID 22213983.
  24. ^ Velazquez Camacho O, Galan C, Swist-Rosowska K, Ching R, Gamalinda M, Fethullah K, De la Rosa-Velazquez I, Engist B, Koschorz B, Shukeir N, Onishi-Seebacher M, van de Nobelen S, Jenuwein T (2017). "Major satellite repeat RNA stabilize heterochromatin retention of Suv39h enzymes by RNA-nucleosome association and RNA:DNA hybrid formation". eLife. 6. doi:10.7554/eLife.25293. PMC 5538826. PMID 28760199.
  25. ^ Allis CD, Jenuwein T (2016). "The molecular hallmarks of epigenetic control". Nature Reviews Genetics. 17 (8): 487–500. doi:10.1038/nrg.2016.59. hdl:11858/00-001M-0000-002C-A8B7-5. PMID 27346641. S2CID 3328936.
  26. ^ Allshire RC, Madhani HD (2018). "Ten principles of heterochromatin formation". Nature Reviews. Molecular Cell Biology. 19 (4): 229–244. doi:10.1038/nrm.2017.119. PMC 6822695. PMID 29235574.
  27. ^ Black JC, Van Rechem C, Whetstine JR (2012). "Histone lysine methylation dynamics: establishment, regulation, and biological impact". Molecular Cell. 48 (4): 491–507. doi:10.1016/j.molcel.2012.11.006. PMC 3861058. PMID 23200123.
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