Involvement of epigenetic factors and metabolism in pluripotency maintenance in C. elegans

Coraggio, Francesca (2019). Involvement of epigenetic factors and metabolism in pluripotency maintenance in C. elegans (Unpublished). (Dissertation, Institute of Cell Biology, Science)

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During the development of multi-cellular organisms, cells undergo differentiation into
distinct cell types. Acquisition of different fates is a consequence of intermingled
multiple external stimuli (non cell autonomous) and internal events (cell autonomous).
The external stimuli include metabolism (in the sense of feeding) and contacts with
neighbouring cells which impact the cell context and modify its life history. This leads
to changes in chromatin organization and the accessibility of target genes to
transcription factors. Cell fate acquisition or differentiation is often a one-way path:
differentiated cells do not change fate. Recently however, the setup of the induction
of pluripotent stem cells (iPSCs) showed that differentiated cells can be
reprogrammed, based on the expression of specific transcription factors. IPSCs
formation correlates with heterochromatin loss.
In C. elegans, the absence of MES-2, the enzymatic core of the Polycomb complex
responsible for histone 3 lysine 27 (H3K27) methylation in heterochromatin, leads to
increased cell fate plasticity during embryonic development, measured as the
capacity to convert embryos into specific tissues by the ectopic expression of cell-fate
specifying transcription factors (cell fate challenge). Here we describe a controlled
cell fate challenge system using single copy transgenes, tractable in both embryonic
and larval stages. In embryos, similar results were obtained as for previous multicopy
arrays, with an extension of the plasticity window in the absence of H3K27
methylation. When muscle differentiation was induced in the first larval stage, worms
lacking H3K27me arrested their development, while an increased number of cells
expressing the muscle marker. Numerous non terminally differentiated lineages were
perturbed, including the V, M and P ones, mostly with unscheduled cell division.
Furthermore, ectopic muscle induction led to the division of bona fide muscle cells.
These organismal and cellular phenotypes could be rescued by knock-down of
multiple components of the Notch pathway, a cell-cell signalling pathway implicated
in asymmetric fate decisions. Interestingly, another regulator of plasticity appears to
be food availability, as starved animals are resistant to cell fate challenge. I showed
that the presence of food leads to visible reorganization of chromatin, potentially
rendering target sites accessible to the specifying transcription factors. The
presence/absence of food appear to be sensed and transduced by the insulin/insulinlike
pathway, as a daf-2 reduction of function mutation ablates the starvation-induced
cell fate challenge resistance. Although I cannot exclude the involvement of other
pathways, this work provides evidence for the function of external stimuli on cell
plasticity determination.

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