CV

Education

1991-1997 Study of Biochemistry, Martin-Luther-Universität, Halle

1997 Diploma in Biochemistry

1997-2002 PhD Thesis "Structure-function analysis of SU(VAR)3-9, an integral component of heterochromatic complexes."Advisor: Prof. G. Reuter, Martin-Luther-Universität, Halle

2002 Ph.D. "summa cum laude"

Professional Positions held

2002-2003 Postdoctoral fellow with Prof. G. Reuter, Martin-Luther-Universität, Halle

2003-2008 Postdoctoral fellow with Prof. T. Jenuwein, Institute of Molecular Pathology (I.M.P.), Vienna

since 2008 W2-Professor, Adolf-Butenandt-Institute, Faculty of Medicine, Ludwig-Maximilians-Universität München

since 2008 Member of the ‘Center for Integrated Protein Science München’

Research interests

Histone lysine methylation is a central modification to mark functionally distinct chromatin regions. Different methylation states (mono-, di- and trimethylation) or combinations of methylated histone residues are recognized by specific binding proteins that can mediate different biological outputs.

In mammals, H4K20 methylation is one of the broadest chromatin modification and has been implicated in important biological processes, such as heterochromatin formation, telomere function, imprinting, X inactivation, DNA damage repair and cancer progression (see published prior achievements, below). Several enzymes can target the different H4K20 methylation states. H4K20me1 is a very dynamic and cell cycle regulated mark which is induced by Pr-Set7 during G2/M phase. H4K20me2 is the most abundant histone modification with more that 80% of all histone H4 molecules carrying this mark. We previously found that H4K20me3 is established at pericentric heterochromatin in a sequential pathway subsequent to H3K9me3 by the Suv39h enzymes and HP1 binding. We also identified the Suv4-20h enzymes as the two major histone methyltransferases (HMTases) to induce H4K20me2 and me3 states.

To analyze the biological roles of H4K20 methylation states, we have now generated conditional null alleles for the two Suv4-20h genes in the mouse. Suv4-20h double null (dn) mice are perinatally lethal, and have lost nearly all H4K20me3 and H4K20me2 states. The genome-wide transition to an H4K20me1 state results in increased sensitivity to damaging stress, since Suv4-20h dn chromatin is less efficient for DNA double strand break (DSB) repair and prone to chromosomal aberrations. Notably, Suv4-20h dn B cells are defective in immunoglobulin class switch recombination, and Suv4-20h dn deficiency impairs the stem cell pool of lymphoid progenitors. Thus, conversion to an H4K20me1 state results in compromised chromatin that is insufficient to protect genome integrity and to process a DNArearranging differentiation program in the mouse.

In order to better understand the different functions of the distinct H4K20 methylation states it will be important to identify specific H4K20me binding proteins by peptide and nucleosome pull-down in combination with SILAC technology. H4K20me2 and me3 are induced by the same enzymes but have different biological outputs. It will be important to understand the regulation and targeting of the Suv4-20h enzymes by identification of associated proteins (Suv4-20h complexes). Suv4-20h enzymes have a very low expression level and, therefore, the generation of specific antibodies has not been successful. We will generate knock-in mice that add a high-affinity tag (Flag-HA and V5-biotin) to the endogenous locus. This will give us a powerful tool to analyse the genome-wide distribution of Suv4-20h enzymes in relation to H4K20 methylation states, to identify Suv4-20h complexes or associated proteins in different developmental stages and to study the action of Suv4-20h enzymes during the cell cycle. In Suv4-20h dn cells, there is still residual H4K20me2 present which might rescue some of the functions of the Suv4-20h enzymes. We will identify those HMTases that are responsible for this residual methylation by a complementary approach using Drosophila RNAi lines and RNAi knock-down in mammalian cells. Successful identification of these HMTases will be followed by generation and analysis of corresponding knock-out mice. Genomic instability can often be the cause of cancer. We will therefore analyse cancer susceptibility of Suv4-20h dn mice using conditional deletion of Suv4-20h enzymes in different tissues in combination with tumor susceptibility mutants (e.g. p53) and classical tumor models (e.g. E��-myc).

Contact

Prof. Dr. Gunnar Schotta

Adolf-Butenandt-Institut

- Molekularbiologie -

Schillerstr. 44

80336 Munich

Tel: +49-89-2180 75-422

Fax: +49-89-2180 75-425

Gunnar.Schotta@med.uni-muenchen.de

Publications

Pannetier M, Julien E, Schotta G, Tardat M, Arnaud P, Sardet C, Jenuwein T and Feil R. Pr-Set7 and Suv4-20h1/h2 regulate H4 lysine-20 methylation at Imprinting Control Regions. submitted

Schotta G, Sengupta R, Kubicek S, Malin S, Kauer M, Callen E, Celeste A, Pagani M, Opravil S, De La Rosa-Velazquez IA, Espejo A, Bedford M, Nussenzweig A, Busslinger M and Jenuwein T. A chromatin-wide transition to H4K20 mono-methylation impairs genome integrity and programmed DNA rearrangements in the mouse. Mol Cell: in revision

Benetti R, Gonzalo S, Jaco I, Schotta G, Klatt P, Jenuwein T, Blasco MA (2007) Suv4-20h deficiency results in telomere elongation and derepression of telomere recombination. J Cell Biol 178: 925-36

Regha K, Sloane MA, Huang R, Pauler FM, Warczok KE, Melikant B, Radolf M, Martens JH, Schotta G, Jenuwein T, Barlow DP (2007) Active and repressive chromatin are interspersed without spreading in an imprinted gene cluster in the mammalian genome. Mol Cell 27: 353-66

Fodor BD, Kubicek S, Yonezawa M, O'sullivan RJ, Sengupta R, Perez-Burgos L, Opravil S, Mechtler K, Schotta G, Jenuwein T (2006) Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev 20: 1557-62

Ebert A, Lein S, Schotta G, Reuter G. (2006) Histone modification and the control of heterochromatic gene silencing in Drosophila. Chromosome Res. 14: 377-92

Kubicek S, Schotta G, Lachner M, Sengupta R, Kohlmaier A, Perez-Burgos L, Linderson Y, Martens JH, O'Sullivan RJ, Fodor BD, Yonezawa M, Peters AH, Jenuwein T (2006) The role of histone modifications in epigenetic transitions during normal and perturbed development.Ernst Schering Res Found Workshop 57: 1-27

Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, Iyer NG, Perez-Rosado A, Calvo E, Lopez JA, Cano A, Calasanz MJ, Colomer D, Piris MA, Ahn N, Imhof A, Caldas C, Jenuwein T, Esteller M (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37: 391-400

Gonzalo S, Garcia-Cao M, Fraga MF, Schotta G, Peters AH, Cotter SE, Eguia R, Dean DC, Esteller M, Jenuwein T, Blasco MA (2005) Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol 7: 420-8

Schotta G, Lachner M, Sarma K, Ebert A, Sengupta R, Reuter G, Reinberg D, Jenuwein T (2004) A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev 18: 1251-62

Ebert A*, Schotta G*, Lein S, Kubicek S, Krauss V, Jenuwein T, Reuter G. (2004) Su(var) genes regulate the balance between euchromatin and heterochromatin in Drosophila. Genes Dev 18: 2973-83

Lachner M, Sengupta R, Schotta G, Jenuwein T (2004) Trilogies of histone lysine methylation as epigenetic landmarks of the eukaryotic genome. Cold Spring Harb Symp Quant Biol 69: 209-18

Schotta G*, Lachner M*, Peters AH, Jenuwein T (2004) The indexing potential of histone lysine methylation. Novartis Found Symp 259: 22-37

Schotta G, Ebert A, Reuter G (2003) SU(VAR)3-9 is a conserved key function in heterochromatic gene silencing. Genetica 117: 149-58

Schotta G, Ebert A, Dorn R, Reuter G (2003) Position-effect variegation and the genetic dissection of chromatin regulation in Drosophila. Semin Cell Dev Biol 14: 67-75

Schotta G, Ebert A, Krauss V, Fischer A, Hoffmann J, Rea S, Jenuwein T, Dorn R, Reuter G (2002) Central role of Drosophila SU(VAR)3-9 in histone H3-K9 methylation and heterochromatic gene silencing. EMBO J 21: 1121-31

Czermin B, Schotta G, Hulsmann BB, Brehm A, Becker PB, Reuter G, Imhof A (2001) Physical and functional association of SU(VAR)3-9 and HDAC1 in Drosophila. EMBO Rep 2: 915-9

Kuhfittig S, Szabad J, Schotta G, Hoffmann J, Mathe E, Reuter G (2001) pitkin(D), a novel gain-of-function enhancer of position-effect variegation, affects chromatin regulation duringoogenesis and early embryogenesis in Drosophila. Genetics 157: 1227-44

Schotta G, Reuter G (2000) Controlled expression of tagged proteins in Drosophila using a new modular P-element vector system. Mol Gen Genet 262: 916-20

Büchner K, Roth P, Schotta G, Krauss V, Saumweber H, Reuter G, Dorn R (2000) Genetic and molecular complexity of the position effect variegation modifier mod(mdg4) in Drosophila. Genetics 155: 141-57

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. EMBO J 18: 1923-38