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Institut de Biologie StructuraleGrenoble / France

Contact person(s) related to this article / KADLEC Jan

Epigenetic regulators

Team leader : Jan Kadlec


In Eukaryotes, DNA exists in the form of chromatin whose dynamics and chemical modifications control access to and the interpretation of DNA information. Dynamic chromatin structure is essential for the regulation of most DNA associated processes, such as transcription, replication or DNA repair. Various post-translational modifications of histones and DNA exist that can change the chromatin structure and recruit effector proteins, such as transcription factors. While genome-wide research in the field of chromatin and epigenetics generates wealth of data on new regulatory pathways and their implications in development or disease, the molecular details of the mechanisms involved are often poorly understood.
We use an interdisciplinary approach combining biochemical, biophysical and structural analyses (X-ray crystallography and electron microscopy) with genetics and cell biology to provide mechanistic insights into important chromatin modifying enzymes with regard to their epigenetic regulatory functions and their role in human disease. Specifically, we focus on two MOF histone acetyltransferase containing complexes, the Non-Specific Lethal (NSL) complex, which is involved in global transcription control, embryonic stem cell pluripotency and DNA repair with implications in genetic disease and cancer development and the Male Specific Lethal (MSL/DCC) complex, which plays a key role in X-chromosome dosage compensation in Drosophila. Another goal of our work is to structurally and functionally characterize several members of the PRDM histone methyltranserase family to reveal molecular details of their diverse roles in cell differentiation, meiotic recombination or cancer.

Figure 1. Histone acetyltransferase MOF exists within two chromatin complexes that regulate its specificity, targeting and function.

Figure 2. Summary of the structural information on the human MSL complex, including our crystal structures of the MSL1/MSL2 tetramer and of MSL1 in complex with the MRG domain of MSL3 and the HAT domain of MOF.

Keywords

Epigenetics, chromatin, transcription, X-ray crystallography, protein complexes

Team Members

Jan KADLEC, (CR1, INSERM)
Team leader at the IBS Grenoble since 2015
Staff Scientist at EMBL Grenoble 2009-2015
Postdoctoral fellow - University of Oxford, UK
PhD 2005, EMBL Grenoble

Shasha SHI – postdoctoral fellow
Ariadna JUAREZ – postdoctoral fellow
Anne-Emmanuelle FOUCHER – Ingénieur d’études (CNRS)

Selected Publications

(* corresponding author)

• Dias, J., Nguyen, N., Georgiev, P., Gaub, A., Brettschneider, J., Cusack, S., Kadlec, J.* and Akhtar, A.* Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex. Genes Dev. 28: 929-942 (2014)

• Wu, H., Mathioudakis, N., Diagouraga, B., Dong A., Dombrovski, L., Baudat. F., Cusack, S., de Massy, B.* and Kadlec, J.* Molecular basis for the regulation of the H3K4 methyltransferase activity of PRDM9.
Cell Rep. 5:13-20 (2013)

• Hallacli, E., Lipp, M., Georgiev, P., Spielman, C., Cusack, S., Akhtar, A.* and Kadlec, J.* MSL1-mediated dimerization of the dosage compensation complex is essential for male X-chromosome regulation in Drosophila. Mol. Cell 48:587-600 (2012)

• Kadlec, J., Hallacli, E., Lipp, M., Holz, H., Sanchez-Weatherby, J., Cusack, S.* and Akhtar, A.* Structural basis for MOF and MSL3 recruitment into the dosage compensation complex by MSL1.
Nat. Struct. Mol. Biol. 18:142-149 (2011)

• Kadlec, J., Loureiro, S., Abrescia, N.G.A., Stuart, D.I. and Jones, I.M. The postfusion structure of baculovirus gp64 supports a unified view of viral fusion machines. Nat. Struct. Mol. Biol. 15: 1024-30 (2008)

• Kadlec, J., Izaurralde, E. and Cusack, S. The structural basis for the interaction between nonsense-mediated mRNA decay factors UPF2 and UPF3. Nat. Struct. Mol. Biol. 11, 330-337 (2004)

Funding

Full list of publications

(* corresponding author)

Touat-Todeschini, L., Shichino, Y., Dangin, M., Thierry-Mieg, N., Gilquin, B., Hiriart, E., Sachidanandam, R., Lambert, E., Brettschneider, J., Reuter, M., Kadlec, J., Pillai, R., Yamashita, A., Yamamoto, M., and Verdel. A. Selective termination of lncRNA transcription promotes heterochromatin silencing and cell differentiation EMBO J. e201796571 (2017)

El Omari, K., Iourin, O., Kadlec, J., Harlos, K., Sutton, G., Grimes, J.M., and Stuart, D.I. Unexpected structure for the N-terminal domain of Hepatitis C virus envelope glycoprotein E1. Nat. Commun. 5:4874 doi: 10.1038/ncomms5874 (2014)

El Omari, K., Iourin, O., Kadlec,J., Fearn, R., Hall, D.R., Harlos, K., Grimes, J.M., and Stuart, D.I. Pushing the limits of Sulfur-SAD phasing, de novo structure solution of the N-terminal domain of the ectodomain of HCV E1. Acta Crystallogr. D Biol. Crystallogr. 70:2197-2203 (2014)

Xiol, J., Spinelli, P., Laussmann, M.A., Homolka, D., Yang, Z., Cora, E., Couté, Y., Conn, S., Kadlec, J., Sachidanandam, R., Kaksonen, M., Cusack, S., Ephrussi A., and Pillai, R.S. RNA clamping by Vasa assembles a piRNA Amplifier complex on transposon transcripts. Cell, 157:1698-711 (2014)

Dias, J., Nguyen, N., Georgiev, P., Gaub, A., Brettschneider, J., Cusack, S., Kadlec, J.* and Akhtar, A.* Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex. Genes Dev. 28: 929-942 (2014)

Guilligay, D., Kadlec, J., Crepin, T., Lunardi,T., Bouvier, D., Kochs, G., Ruigrok, R. and Cusack, S., Comparative structural and functional analysis of orthomyxovirus polymerase cap-snatching domains. PLOS One 9:e84973 (2014)

Wu, H., Mathioudakis, N., Diagouraga, B., Dong A., Dombrovski, L., Baudat. F., Cusack, S., de Massy, B.* and Kadlec, J.* Molecular basis for the regulation of the H3K4 methyltransferase activity of PRDM9. Cell Rep. 5:13-20 (2013)

Najmanova, L., Kutejova, E., Kadlec, J., Polan, M., Olsovska, J., Benada, O., Novotna, J., Kamenik, Z., Halada, P., Bauer, J., and Janata., J Characterization of N-demethyllincosamide methyltransferases LmbJ and CcbJ. ChemBioChem 14:2259-62 (2013)

Iourin, O., Harlos, K., El Omari, K., Lu, W., Kadlec, J., Iqbal, M., Meier, C., Palmer A., Jones, I., Thomas, C., Brownlie, J., Grimes, J.M., and Stuart, D.I Expression, purification and crystallization of the ectodomain of the envelope glycoprotein E2 from Bovine viral diarrhoea virus. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 69:35-38 (2013)

Hallacli, E., Lipp, M., Georgiev, P., Spielman, C., Cusack, S., Akhtar, A.* and Kadlec, J.* MSL1-mediated dimerization of the dosage compensation complex is essential for male X-chromosome regulation in Drosophila. Mol. Cell 48:587-600 (2012)

O’Flynn, N.M.J., Patel, A., Kadlec, J. and Jones I.M. Improving promiscuous mammalian cell entry by the baculovirus AcMNPV. Biosci. Rep. 33:23-36 (2012)

Mathioudakis, N., Palencia, A., Kadlec, J., Round, A., Tripsianes, K., Sattler, M., Pillai, R.S. and Cusack, S. The multiple Tudor domain-containing protein TDRD1 is a molecular scaffold for mouse Piwi proteins and piRNA biogenesis factors. RNA 18:2056-72 (2012)

Kadlec, J., Hallacli, E., Lipp, M., Holz, H., Sanchez-Weatherby, J., Cusack, S.* and Akhtar, A.* Structural basis for MOF and MSL3 recruitment into the dosage compensation complex by MSL1. Nat. Struct. Mol. Biol. 18:142-149 (2011)

Raja, S.J., Charapitsa, I., Conrad, T., Vaquerizas, J.M., Gebhardt, P., Holz, H., Kadlec, J., Fraterman, S., Luscombe, N.M. and Akhtar, A. The nonspecific lethal complex is a transcriptional regulator in Drosophila. Mol. Cell 38:827-41 (2010)

Sanchez-Weatherby, J., Bowler, M.W., Huet, J., Gobbo, A., Felisaz, F., Lavault, B., Moya, R., Kadlec, J., Ravelli, R.B. and Cipriani, F. Improving diffraction by humidity control: a novel device compatible with X-ray beamlines. Acta Crystallogr. D Biol. Crystallogr. 65:1237-46. (2009)

Clerici M., Mourão, A., Gutsche, I., Gehring, N.H, Hentze, M., Kulozik A., Kadlec J., Sattler M., and Cusack S. Unusual bipartite mode of interaction between the nonsense mediated decay factors UPF1 and UPF2. EMBO J. 28:2293-2306 (2009).

Kadlec, J., Loureiro, S., Abrescia, N.G.A., Stuart, D.I. and Jones, I.M. The postfusion structure of baculovirus gp64 supports a unified view of viral fusion machines. Nat. Struct. Mol. Biol. 15: 1024-30 (2008)

Walter, T.S. Mancini, E.J., Kadlec, J., Grahem, S.C., Assenberg, R., Ren, J., Sainsbury, S., Owens, R.J., Stuart, D.I., Grimes, J.M. and Harlos, K. Semi-automated microseeding of nanolitre crystallization experiments. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 64, 14-8 (2008)

Kadlec, J., Guilligay, D., Ravelli, R.B. and Cusack, S. Crystal structure of the UPF2-interacting domain of nonsense-mediated mRNA decay factor UPF1. RNA 12, 1817–1824 (2006)

Kadlec, J., Izaurralde, E. and Cusack, S. The structural basis for the interaction between nonsense-mediated mRNA decay factors UPF2 and UPF3. Nat. Struct. Mol. Biol. 11, 330-337 (2004)

Bracher, A., Kadlec, J., Betz, H. and Weissenhorn, W. X-ray structure of a neuronal complexin-SNARE complex from squid.
J. Biol. Chem. 277, 26517-26523 (2002)