“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.
Figure 1: Overview of major epigenetic changes during mouse development.
Figure 2: Interplay between chromatin changes and hallmarks of DNA repair during germline epigenetic reprogramming.
Hill PWS, Leitch HG, Requena CE, Sun Z, Amouroux R, Roman-Trufero M, Borkowska M, Terragni J, Vaisvila R, Linnett S, Bagci H, Dharmalingham G, Haberle V, Lenhard B, Zheng Y, Pradhan S, Hajkova P. (2018). Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature 555, 392.
Leitch HG, Hajkova P. (2018). MATERNAL OBESITY Eggs sense high-fat diet. Nature Genetics 50, 318-319.
Rosic S, Amouroux R, Requena CE, Gomes A, Emperle M, Beltran T, Rane JK, Linnett S, Selkirk ME, Schiffer PH, Bancroft AJ, Grencis RK, Jeltsch A, Hajkova P, Sarkies P. (2018). Evolutionary analysis indicates that DNA alkylation damage is a byproduct of cytosine DNA methyltransferase activity. Nature Genetics 50, 452–459.
Benesova M, Trejbalova K, Kucerova D, Vernerova Z, Hron T, Szabo A, Amouroux R, Klezl P, Hajkova P, Hejnar J. (2017). Overexpression of TET dioxygenases in seminomas associates with low levels of DNA methylation and hydroxymethylation. Molecular Carciogenesis 56, 1837-1850.
Ferry L, Fournier A, Tsusaka T, Adelmant G, Shimazu T, Matano S, Kirsh O, Amouroux R, Dohmae N, Suzuki T, Filion GJ, Deng W, de Dieuleveult M, Fritsch L, Kudithipudi S, Jeltsch A, Leonhardt H, Hajkova P, Marto JA, Arita K, Shinkai Y, Defossez P-A. (2017). Methylation of DNA Ligase 1 by G9a/GLP Recruits UHRF1 to Replicating DNA and Regulates DNA Methylation. Molecular Cell 67, 550.
Izzo A, Ziegler-Birling C, Hill PWS, Brondani L, Hajkova P, Torres-Padilla M-E, Schneider Rclose. (2017). Dynamic changes in H1 subtype composition during epigenetic reprogramming. Journal of Cell Biology 216, 3017-3028.
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 18, 225.
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 oogenesis. Mol cell 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 34(10), 1296-308. Pii: e201490649.
Hill PW, Amouroux R, Hajkova P. (2014). DNA demethylation, tet proteins and 5-hydroxymethylcytosine in epigenetic reprogramming: An emerging complex story. Genomics 104, 324-333.
Leitch HG, McEwen KR, Turp A, Encheva V, Carroll T, Grabole N, Mansfield W, Nashun B, Knezovich JG, Smith A, Surani MA, 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 B 366(1575), 2266–2273.
Hajkova P, Jeffries SJ, Lee C, Miller N, Jackson SP, Surani MA. (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 UC, Cesari F, Lee C, Almouzni G, Schneider R, Surani MA. (2008). Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452(7189), 877–881.
Surani MA, Hayashi K, Hajkova P. (2007). Genetic and epigenetic regulators of pluripotency. Cell 128(4), 747–762.