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Dr Jose Silva

Abstract:

Nuclear reprogramming occurs when a somatic cell nucleus is reverted to a pluripotent state. This can be achieved by several processes such as nuclear transfer, cell fusion or the use of defined factors. In the case of the latter this was first described by Takahashi and Yamanaka in 2006 where, by transfecting fibroblasts with Oct4, Sox2, c-Myc and Klf4, pluripotent cells were generated. This process was named induced pluripotency and the cells generated became induced pluripotent stem cells (iPS). iPS cell generation is regulated by Nanog and this can be enhanced by its exogenous expression. The mode of action of Nanog in reprogramming was unknown until recently, when it was demonstrated that it acts in concert with the epigenetic modifiers Tet1 and Tet2. Using a similar system we would like to investigate other Nanog interactors with an epigenetic role and determine if this partnership has an effect in naive induced pluripotency. To achieve this we will use transgenes for Nanog and Nanog interactors. First we will test their putative reprogramming effect in somatic cell reprogramming intermediates (pre-iPS). In the event of antagonistic outcomes for somatic cell reprogramming on the part of the Nanog interactors, we will test the effect of their knockdown during this process. Additional research will characterise expression of these interactors upon reprogramming. The results obtained will allows us to form a more complete view of how epigenetic modifiers work with or against Nanog to influence the process of nuclear reprogramming.

References:

  1. Stuart HT, van Oosten AL, Radzisheuskaya A, Martello G, Miller A, Dietmann S, Nichols J, Silva JCR. NANOG amplifies STAT3 activation and they synergistically induce the naïve pluripotent program. Current Biology (2014). 24, 1–7, February 3 doi: 10.1016/j.cub.2013.12.040. 
  2. Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV, Fidalgo M, Saunders A, Lawrence M, Dietmann S, Das S ,Levasseur DN, Li Z, Xu M, Reik W, Wang J#, Silva JCR#. Nanog-dependent function of Tet1 and Tet2 in establishment of pluripotency. Nature. (2013) doi:10.1038/nature11925.
  3. Silva J#, Nichols J, Theunissen TW, Guo G, van Oosten AL, Barrandon O, Wray J,Chambers I, Yamanaka S, Smith A#. Nanog is the Gateway to the Pluripotent Ground State. Cell. (2009) Aug 21;138(4):722-37

Dr José Silva

Dr José Silva
Department of Biochemistry
Office Phone: 01223 760282

Biography:

The Silva lab research is centred on the biology of nuclear reprogramming, that is, the conversion of a differentiated epigenome back into a pluripotent epigenome. In the mouse system this corresponds to the generation of induced naive pluripotent cells. This process has a parallel to normal embryonic development, more precisely to the establishment of the naive pluripotent epiblast. In vivo, naive pluripotent cells give rise to all cell types of the adult animal. The Silva lab has developed a unique cell system to better investigate the process of induced naive pluripotency. This cell system is comprised of different and key cell state transitions which are unveiling surprising and exciting new discoveries on the biology of defined factors. Examples of these were the identification of Nanog and of the culture environment as key players for the establishment of a naive pluripotent cell state. Our current research focus not only on identifying further key players but also on determining the molecular mechanisms by which these work. Fully understanding induced pluripotency and better characterising iPS and ES cells is indispensible before these can be used in biomedical applications.

Termination details:

The Silva lab research is centred on the biology of nuclear reprogramming, that is, the conversion of a differentiated epigenome back into a pluripotent epigenome. In the mouse system this corresponds to the generation of induced naive pluripotent cells. This process has a parallel to normal embryonic development, more precisely to the establishment of the naive pluripotent epiblast. In vivo, naive pluripotent cells give rise to all cell types of the adult animal. The Silva lab has developed a unique cell system to better investigate the process of induced naive pluripotency. This cell system is comprised of different and key cell state transitions which are unveiling surprising and exciting new discoveries on the biology of defined factors. Examples of these were the identification of Nanog and of the culture environment as key players for the establishment of a naive pluripotent cell state. Our current research focus not only on identifying further key players but also on determining the molecular mechanisms by which these work. Fully understanding induced pluripotency and better characterising iPS and ES cells is indispensible before these can be used in biomedical applications.