Thomas Jenuwein

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Thomas Jenuwein
T. Jenuwein.jpg
April 2019
Born (1956-12-10) 10 December 1956 (age 66)
Lohr am Main, Germany
Nationality German
Alma mater EMBL, Heidelberg
Scientific career
Fields Epigenetics
Institutions UCSF,
Research Institute of Molecular Pathology,
Max Planck Institute of Immunobiology and Epigenetics
Website www.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.

Contents

Biography

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

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

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

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.

Related Research Articles

<span class="mw-page-title-main">Histone</span> Family proteins package and order the DNA into structural units called nucleosomes.

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

<span class="mw-page-title-main">Epigenetics</span> Study of DNA modifications that do not change its sequence

In biology, epigenetics are stable heritable traits that cannot be explained by changes in DNA sequence, and the study of a type of stable change in cell function that does not involve a change to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. They can lead to cancer.

<span class="mw-page-title-main">Histone methyltransferase</span> Histone-modifying enzymes

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

<span class="mw-page-title-main">Histone H3</span> One of the five main histone proteins

Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'beads on a string' structure. Histone proteins are highly post-translationally modified however Histone H3 is the most extensively modified of the five histones. The term "Histone H3" alone is purposely ambiguous in that it does not distinguish between sequence variants or modification state. Histone H3 is an important protein in the emerging field of epigenetics, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

The family of heterochromatin protein 1 (HP1) consists of highly conserved proteins, which have important functions in the cell nucleus. These functions include gene repression by heterochromatin formation, transcriptional activation, regulation of binding of cohesion complexes to centromeres, sequestration of genes to the nuclear periphery, transcriptional arrest, maintenance of heterochromatin integrity, gene repression at the single nucleosome level, gene repression by heterochromatization of euchromatin, and DNA repair. HP1 proteins are fundamental units of heterochromatin packaging that are enriched at the centromeres and telomeres of nearly all eukaryotic chromosomes with the notable exception of budding yeast, in which a yeast-specific silencing complex of SIR proteins serve a similar function. Members of the HP1 family are characterized by an N-terminal chromodomain and a C-terminal chromoshadow domain, separated by a hinge region. HP1 is also found at some euchromatic sites, where its binding can correlate with either gene repression or gene activation. HP1 was originally discovered by Tharappel C James and Sarah Elgin in 1986 as a factor in the phenomenon known as position effect variegation in Drosophila melanogaster.

<span class="mw-page-title-main">SUV39H1</span> Protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase SUV39H1 is an enzyme that in humans is encoded by the SUV39H1 gene.

<span class="mw-page-title-main">CBX5 (gene)</span> Protein-coding gene in humans

Chromobox protein homolog 5 is a protein that in humans is encoded by the CBX5 gene. It is a highly conserved, non-histone protein part of the heterochromatin family. The protein itself is more commonly called HP1α. Heterochromatin protein-1 (HP1) has an N-terminal domain that acts on methylated lysines residues leading to epigenetic repression. The C-terminal of this protein has a chromo shadow-domain (CSD) that is responsible for homodimerizing, as well as interacting with a variety of chromatin-associated, non-histone proteins.

<span class="mw-page-title-main">EHMT1</span> Protein-coding gene in the species Homo sapiens

Euchromatic histone-lysine N-methyltransferase 1, also known as G9a-like protein (GLP), is a protein that in humans is encoded by the EHMT1 gene.

Protein methylation is a type of post-translational modification featuring the addition of methyl groups to proteins. It can occur on the nitrogen-containing side-chains of arginine and lysine, but also at the amino- and carboxy-termini of a number of different proteins. In biology, methyltransferases catalyze the methylation process, activated primarily by S-adenosylmethionine. Protein methylation has been most studied in histones, where the transfer of methyl groups from S-adenosyl methionine is catalyzed by histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.

H3K9me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 9th lysine residue of the histone H3 protein and is often associated with heterochromatin.

H3K9me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 9th lysine residue of the histone H3 protein. H3K9me2 is strongly associated with transcriptional repression. H3K9me2 levels are higher at silent compared to active genes in a 10kb region surrounding the transcriptional start site. H3K9me2 represses gene expression both passively, by prohibiting acetylation as therefore binding of RNA polymerase or its regulatory factors, and actively, by recruiting transcriptional repressors. H3K9me2 has also been found in megabase blocks, termed Large Organised Chromatin K9 domains (LOCKS), which are primarily located within gene-sparse regions but also encompass genic and intergenic intervals. Its synthesis is catalyzed by G9a, G9a-like protein, and PRDM2. H3K9me2 can be removed by a wide range of histone lysine demethylases (KDMs) including KDM1, KDM3, KDM4 and KDM7 family members. H3K9me2 is important for various biological processes including cell lineage commitment, the reprogramming of somatic cells to induced pluripotent stem cells, regulation of the inflammatory response, and addiction to drug use.

H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.

H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies.

H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono-methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for genome integrity including DNA damage repair, DNA replication and chromatin compaction.

H3K36me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 36th lysine residue of the histone H3 protein.

H3K36me is an epigenetic modification to the DNA packaging protein Histone H3, specifically, the mono-methylation at the 36th lysine residue of the histone H3 protein.

H3R42me is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the mono-methylation at the 42nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

References

  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. 1 2 3 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. 1 2 3 4 "Epigenetics, Second Edition". cshlpress.com.
  8. ↑ . HSTalks.
  9. ↑ . 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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