Each of the some 20’000 genes constituting our genome is present in two copies, in the nucleus of each one of our cells, one inherited from our mother and the other from our father. While most genes are then expressed from both of these copies, or alleles, for about a hundred genes one of them is silenced through a set of so-called epigenetic modifications known as imprinting, which is established during the formation of the egg and the sperm, and needs to be maintained after fertilization. Imprinted genes play key developmental roles, and genetic defects in imprinting accordingly cause growth-related or neuro-developmental disorders such as transient neonatal diabetes, Beckwith-Wiederman, Silver-Russel, Angelman or Prader-Willy syndromes, as well as cases of molar pregnancy and infertility by oligospermia. Mutations in ZFP57, an important effector of this process, are responsible for transient neonatal diabetes mellitus (TNDM), a rare form of diabetes that presents in infancy, resolves within a few months, but frequently recurs later in life. Our work has shed important mechanistic insight on the mechanism of action of ZFP57, and more broadly on how related proteins, collectively coined KRAB-ZFPs, establish marks typical of imprinting such as DNA methylation during early embryogenesis. The present project aimed a capitalizing on these results to decipher the mechanism of ZFP57-mediated control of imprinting, more broadly to expand our understanding of human diseases resulting from defects in imprinting, and ultimately to facilitate the diagnosis and possibly the treatment of these and related affections, which may be facilitated by the launching of a start-up company focused towards this objective.
What is special about the project?
Transient neonatal diabetes, Beckwith-Wiederman, Silver-Russel, Angelman or Prader-Willy syndromes are rare diseases linked to defects in imprinting, a biological phenomenon that has its roots in so-called epigenetics, the clinical importance of which is increasingly recognized. This project is thus both in line with the objectives of the Gebert Rüf Foundation and very timely. Over the last few years, our laboratory has taken a leading role in the study of a family of effectors of epigenetic modifications including imprinting, and our long-term objective is to examine how mutations or polymorphism in the genetic components of this process may condition inter-individual differences in susceptibility to human diseases. The present project capitalized on our know-how in this field to decipher the mechanisms controlling imprinting, more broadly to expand our understanding of human diseases resulting from defects in these events, and ultimately to facilitate the diagnosis and possibly the treatment of these affections.
We broadly reached the specific aims set at the beginning of the funding period, even taking this work to broader horizons. We first succeeded in mapping the human genomic determinants of imprinting, and demonstrated how this process is protected by very specific mechanisms during early embryogenesis, while its subsequent maintenance relies on more generic events. We then determined how the protein and DNA components of the imprinting machinery interact with each other, fighting off influences that would otherwise erase the maternally and paternally inherited imprinting marks. We went on to identify the genomic targets of most human factors belonging to the same family as ZFP57. We are pursuing our effort under other funding auspices, to explore how imprinting constitutes a paradigm for the trans-generational inheritance of epigenetic marks.
For a structuring standpoint, the funding of Geber Rüf Stiftung served as a basis to obtain additional support, notably from the European Union, and planted the seed of work now exploited for the launching of a start-up.
Trono, D. Transposable Elements, Polydactyl Proteins, and the Genesis of Human-Specific Transcription Networks. Cold Spring Harb Symp Quant Biol (2016).
Kapopoulou, A., Mathew, L., Wong, A., Trono, D. & Jensen, J.D. The evolution of gene expression and binding specificity of the largest transcription factor family in primates. Evolution 70, 167-80 (2016).
Ecco, G., Rowe, H.M. & Trono, D. A Large-Scale Functional Screen to Identify Epigenetic Repressors of Retrotransposon Expression. Methods Mol Biol 1400, 403-17 (2016).
Ecco, G., Cassano, M., Kauzlaric, A., Duc, J., Coluccio, A., Offner, S., Imbeault, M., Rowe, H.M., Turelli, P. & Trono, D. Transposable elements and their KRAB-ZFP controllers regulate gene expression in adult tissues. Dev Cell 36, 611-623 (2016).
Singh, K., Cassano, M., Planet, E., Sebastian, S., Jang, S.M., Sohi, G., Faralli, H., Choi, J., Youn, H.D., Dilworth, F.J. & Trono, D. A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation. Genes Dev 29, 513-25 (2015).
Rauwel, B., Jang, S.M., Cassano, M., Kapopoulou, A., Barde, I. & Trono, D. Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch. Elife 4(2015).
Friedli, M. & Trono, D. The Developmental Control of Transposable Elements and the Evolution of Higher Species. Annu Rev Cell Dev Biol 31, 429-51 (2015).
Fasching, L., Kapopoulou, A., Sachdeva, R., Petri, R., Jonsson, M.E., Manne, C., Turelli, P., Jern, P., Cammas, F., Trono, D. & Jakobsson, J. TRIM28 Represses Transcription of Endogenous Retroviruses in Neural Progenitor Cells. Cell Rep 10, 20-8 (2015).
Dietrich, J.E., Panavaite, L., Gunther, S., Wennekamp, S., Groner, A.C., Pigge, A., Salvenmoser, S., Trono, D., Hufnagel, L. & Hiiragi, T. Venus trap in the mouse embryo reveals distinct molecular dynamics underlying specification of first embryonic lineages. EMBO Rep 16, 1005-21 (2015).
Castro-Diaz, N., Friedli, M. & Trono, D. Drawing a fine line on endogenous retroelement activity. Mob. Genet. Elements 5, 1-6 (2015).
Turelli, P., Castro-Diaz, N., Marzetta, F., Kapopoulou, A., Raclot, C., Duc, J., Tieng, V., Quenneville, S. & Trono, D. Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements. Genome Res 24, 1260-70 (2014).
Imbeault, M. & Trono, D. As Time Goes by: KRABs Evolve to KAP Endogenous Retroelements. Dev Cell 31, 257-8 (2014).
Gubelmann, C., Schwalie, P.C., Raghav, S.K., Roder, E., Delessa, T., Kiehlmann, E., Waszak, S.M., Corsinotti, A., Udin, G., Holcombe, W., Rudofsky, G., Trono, D., Wolfrum, C. & Deplancke, B. Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network. Elife 3(2014).
Friedli, M., Turelli, P., Kapopoulou, A., Rauwel, B., Castro-Diaz, N., Rowe, H.M., Ecco, G., Unzu, C., Planet, E., Lombardo, A., Mangeat, B., Wildhaber, B.E., Naldini, L. & Trono, D. Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotency. Genome Res 24, 1251-9 (2014).
Castro-Diaz, N., Ecco, G., Coluccio, A., Kapopoulou, A., Yazdanpanah, B., Friedli, M., Duc, J., Jang, S.M., Turelli, P. & Trono, D. Evolutionally dynamic L1 regulation in embryonic stem cells. Genes Dev 28, 1397-409 (2014).
Rowe, H.M., Kapopoulou, A., Corsinotti, A., Fasching, L., Macfarlan, T.S., Tarabay, Y., Viville, S., Jakobsson, J., Pfaff, S.L. & Trono, D. TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells. Genome Res 23, 452-61 (2013).
Rowe, H.M., Friedli, M., Offner, S., Verp, S., Mesnard, D., Marquis, J., Aktas, T. & Trono, D. De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET. Development 140, 519-29 (2013).
Marquez, C., Poirier, G.L., Cordero, M.I., Larsen, M.H., Groner, A., Marquis, J., Magistretti, P.J., Trono, D. & Sandi, C. Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression. Transl Psychiatry 3, e216 (2013).
Jaguva Vasudevan, A.A., Perkovic, M., Bulliard, Y., Cichutek, K., Trono, D., Haussinger, D. & Munk, C. Prototype foamy virus Bet impairs the dimerization and cytosolic solubility of human APOBEC3G. J Virol 87, 9030-40 (2013).
Corsinotti, A., Kapopoulou, A., Gubelmann, C., Imbeault, M., Santoni de Sio, F.R., Rowe, H.M., Mouscaz, Y., Deplancke, B. & Trono, D. Global and stage specific patterns of Kruppel-associated-box zinc finger protein gene expression in murine early embryonic cells. PLoS One 8, e56721 (2013).
Barde, I., Rauwel, B., Marin-Florez, R.M., Corsinotti, A., Laurenti, E., Verp, S., Offner, S., Marquis, J., Kapopoulou, A., Vanicek, J. & Trono, D. A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy. Science 340, 350-3 (2013).
Andrey, G., Montavon, T., Mascrez, B., Gonzalez, F., Noordermeer, D., Leleu, M., Trono, D., Spitz, F. & Duboule, D. A switch between topological domains underlies HoxD genes collinearity in mouse limbs. Science 340, 1234167 (2013).
Persons involved in the project
Didier Trono, project leader didier.
Séverine Reynard severine.
Andrea Coluccio, graduate student andrea.
Alberto de Iacco, post-doctoral fellow alberto.
Priscilla Turelli, senior scientist priscilla.
Last update to this project presentation 16.07.2018