2010 - 2013
Dates of Study: Oct 2010 - Sept 2013
PhD Supervisor: Dr José Silva
Studentship Sponsor: The Darwin Trust of Edinburgh Postgraduate Scholarship
Thesis Title: Mechanisms of induced pluripotency: role of histone variant macroH2A and transcription factor Oct4
Public Outreach: Participated in the running of the Stem Cell stand at the Cambridge Science Festival in 2011.
Following her PhD, Aliaksandra took up a PostDoc position in Dr José Silva's lab at The Stem Cell Institute, University of Cambridge.
In October 2014 Aliaksandra began working as a Postdoctoral Associate with Professor Kristian Helin at The Biotech Research and Innovation Centre, University of Copenhagen in Denmark. While in Prof Helin's lab, Aliaksandra was awarded the prestigious EMBO Postdoctoral Fellowship to continue her career in the lab in Denmark.
Dose-dependent requirements for Oct4 in cells state transitions.
Legend: The combined transduction and transfection of reprogramming transgenes into Oct4-/- somatic cells results in the generation of highly proliferative reprogramming intermediates. Upon exposure to 2i/LIF culture conditions some of these undergo conversion to a pluripotent cell state. Remarkably, independently of Oct4 expression level in reprogramming intermediates generated iPSCs-/- always show an invariable ESC level of Oct4 expression. Once cells have entered a pluripotent state they can be maintained within a range of Oct4 expression from an ESC level to up to 7-fold less without loss of self-renewing capacity. This indicates a specific requirement for a defined Oct4 level for the acquisition rather than maintenance of the naïve pluripotent state. As shown before for ESCs, complete abolishment of Oct4 expression in iPSCs-/- leads to differentiation towards trophectoderm lineage. Surprisingly, pluripotent cells with constitutive ESC level of Oct4 can efficiently differentiate into the three germ layers and germline upon the provision of appropriate signalling cues. At the same time ESCs/iPSCs with low Oct4 levels demonstrate enhanced self-renewing capabilities independently of culture conditions and fail to exit the pluripotent state upon the induction of differentiation. Overall these data demonstrate that Oct4 actively controls cell state transitions taking place during the entry to and exit from the naïve pluripotent cell state.
My research thesis describes the identification of an epigenetic mechanism stabilizing the differentiated cell state and acting as a barrier to induced pluripotency (incorporation of histone variant macroH2A) and the investigation of the requirement of the transcription factor Oct4 during the process of induced pluripotency.
- Radzisheuskaya A, Chia GLB, dos Santos RL, Theunissen TW, Castro LF, Nichols J, Silva JC (2013). A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages. Nat Cell Biol. 2013 Apr 30. doi: 10.1038/ncb2742.
- Pasque V*, Radzisheuskaya A*, Gillich A, Halley-Stott RP, Panamarova M, Zernicka-Goetz M, Surani MA, Silva JC (2012). Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency. J Cell Sci. 2012 Dec 15; 125(Pt 24):6094-104. *Equal contribution
- Theunissen TW, Costa Y, Radzisheuskaya A, van Oosten AL, Lavial F, Pain B, Castro LF, Silva JC (2011). Reprogramming capacity of Nanog is functionally conserved in vertebrates and resides in a unique homeodomain. Development. 2011 Nov; 138(22):4853-65.