“Epigenetic reprogramming encompasses changes in nuclear architecture and epigenetic modifications that lead to a shift in gene expression profile and cell identity.”
Development of any organism starts with a totipotent cell (zygote). Through series of cell divisions and differentiation processes this cell will give rise to the whole organism containing hundreds of specialised cells. While the cells at the onset of development have the capacity to generate all cell types (ie are toti-or pluripotent), this developmental capacity is progressively lost as the cells undertake cell fate decisions. At the molecular level, the memory of these events is laid down in a complex layer of epigenetic modifications at both the DNA and the chromatin level.
The main research focus of our laboratory is trying to understand molecular processes that underlie global erasure of epigenetic information. As in vitro cellular reprogramming systems are notoriously inefficient and heterogeneous in outcome, we focus on the epigenetic reprogramming events that occur naturally in vivo during mouse development (in the mouse zygote and in the early mouse germ cells). We are particularly interested in:
1) the erasure and dynamics of DNA modifications during these processes and
2) the chromatin assembly/disassembly and underlying histone dynamics.
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.
Luo C, Hajkova P, Ecker JR. (2018). Dynamic DNA methylation: In the right place at the right time. Science, 361, 1336-1340.
Leitch HG, Hajkova P. (2018). Eggs sense high-fat diet. Nature Genetics 50(3), 318-319.
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.
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.
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. Molecular 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.