Reprogramming and Chromatin

“Epigenetic reprogramming encompasses changes in nuclear architecture and epigenetic modifications that eventually lead to a shift in gene expression profile”

At the molecular level reprogramming involves the erasure of epigenetic marks including DNA methylation and histone modifications. Our lab uses in vivo models to elucidate molecular mechanisms underlying naturally occurring reprogramming events. The knowledge gained allows us to design in vitro experimental systems and to use biochemical approaches to investigate further molecular details.

We study reprogramming events both in the developing mouse germ line and in the mouse zygote. The former involves both genomewide DNA demethylation and chromatin remodelling, whereas reprogramming the zygote involves genome wide DNA demethylation affecting only the paternal genome a few hours after fertilisation.

As epigenetic reprogramming plays a pivotal role in the dedifferentiation and the reversal of cell fate decisions, investigation of molecular pathways underlying such processes provides direct mechanistic links to regeneration and cancer.

Reprogramming and Chromatin

Figure 1: Overview of major epigenetic changes during mouse development.

Reprogramming and Chromatin

Figure 2: Interplay between chromatin changes and hallmarks of DNA repair during germline epigenetic reprogramming.


Selected Publications

Amouroux R, Nashun B, Shirane K, Nakagawa S, Hill PW, D’Souza Z, Nakayama M, Matsuda M, Turp A, Ndjetehe E, Encheva V, Kudo NR, Koseki H, Sasaki H, Hajkova P. (2016) De novo DNA methylation drives 5hmC accumulation in mouse zygotes. Nat Cell Biol. [Epub ahead of print]

Nashun B, Hill PW, Smallwood SA, Dharmalingam G, Amouroux R, Clark SJ, Sharma V, Ndjetehe E, Pelczar P, Festenstein RJ, Kelsey G, Hajkova P. (2015) Continuous histone replacement by Hira is essential for normal transcriptional regulation and de novo DNA methylation during mouse oogenesisMol cell, 19;60(4)611-25.

Nashun B, Hill PW, Hajkova P. (2015). Reprogramming of cell fate: epigenetic memory and the erasure of memories past. EMBO Journal. Pii: e201490649.

Supek F, Lehner B, Hajkova P, et al. (2014). Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates. Plos Genetics, 10.

Hill, P. W., Amouroux, R., & Hajkova, P. (2014). DNA demethylation, tet proteins and 5-hydroxymethylcytosine in epigenetic reprogramming: An emerging complex story. Genomics, 104, 324-333.

Leitch, H. G., McEwen, K. R., Turp, A., Encheva, V., Carroll, T., Grabole, N., Mansfield, W., Nashun, B., Knezovich, J. G., Smith, A., Surani, M. A., & Hajkova, P. (2013). Naive pluripotency is associated with global DNA hypomethylation. Nature Structural & Molecular Biology, 20(3), 311–316.

Hajkova, P. (2011). Epigenetic reprogramming in the germline: towards the ground state of the epigenome. Philosophical Transactions of the Royal Society of London. Series B, Biological sciences, 366(1575), 2266–2273.

Hajkova, P., Jeffries, S. J., Lee, C., Miller, N., Jackson, S. P., & Surani, A. A. (2010). Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway. Science, 329(5987), 78–82.

Hajkova, P. (2010). Epigenetic reprogramming – taking a lesson from the embryo. Current Opinion in Cell Biology, 22(3), 342–350.

Hajkova, P., Ancelin, K., Waldmann, T., Lacoste, N., Lange, U. C., Cesari, F., Lee, C., Almouzni, G., Schneider, R., & Surani, M. A. (2008). Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature, 452(7189), 877–881.

Surani, M. A., Hayashi, K., & Hajkova, P. (2007). Genetic and epigenetic regulators of pluripotency. Cell, 128(4), 747–762.