14 October 2016
Polycomb enables primitive endoderm lineage priming in embryonic stem cells
Illingworth RS*, Hölzenspies JJ*, Roske FV, Bickmore WA, Brickman JM. Polycomb enables primitive endoderm lineage priming in embryonic stem cells. eLife 2016;5:e14926
Illingworth RS*, Hölzenspies JJ*, Roske FV, Bickmore WA, Brickman JM. Polycomb enables primitive endoderm lineage priming in embryonic stem cells. eLife 2016.
Embryonic stem cells (ESCs) hold great promise for regenerative medicine as they can produce copies of themselves indefinitely, i.e. self-renew, and they can form any of the cell types that make up the adult body, a property known as pluripotency. Because of these properties, ESCs can potentially be used to cure a whole host of diseases as they provide an unlimited source of specific cell types and potentially even complete organs that could be used for transplantation.
What makes ESCs able to make many cell types? One principle property of these cells is that they are actually not a single cell type, but a population of cells trying out different choices. However, to stay as a stem cell, ESCs must be able to try out these choices without making an irrovacable decision. In a normal developing embryo, cells from the early embryo are pluripotent in the beginning, but as the body forms, they rapidly chose different destinies and under normal circumstances will never go back.
What is in ESCs that enables them to sample different choices, without making a decision? In this recent paper from the Brickman and Bickmore labs, the choice of ESCs to make some of the cells that normally support the later foetus, known of the primitive endoderm was explored. They found that hundreds of genes began to be read synchronously as ESCs explored the primitive endoderm choice. They found that these synchronous changes in “primitive endoderm genes,” or instructions, was controlled by the machinery that turns genes on and off – the process of transcription. However, if these instructions for being primitive endoderm were being read, what was keeping these cells as ESCs? They also found that a complex normally thought to silence genes, or keep instructions from ever being read, known as Polycomb, had a different role in ESCs. At these primitive endoderm genes, Polycomb was found to book mark these instructions, allowing them to be read, but not expanded on. In other words, they found that Polycomb allowed ESCs to sample the primitive endoderm instructions, without committing to it. When Polycomb was removed, it did not impact on the ability of ESCs to read the primitive endoderm genes, but rather increased the chance, that ESCs could spontaneously chose to become endoderm, rather than remaining as a stem cell. These finding suggest that Polycomb maybe an important determinant of stem cell identity, allow cells to explore different choices, providing them with potency, while keeping them as stem cells and blocking their commitment.
These studies suggest that by understanding and manipulating Polycomb it might be possible to trigger stem cell differentiation and induce new types of stem cells at different points in embryonic differentiation. They also shed light on the role of Polycomb in cancer.
* First author
About the first co-author:
Jurriaan Jochem Hölzenspies is a postdoc at the Brickman group. His research inteerst lies in the role of transcriptional regulation by chromatin modifying proteins with a focus on polycomb proteins in maintaining pluripotency during embryonic stem cell self-renewal and in the process of lineage commitment during endoderm differentiation. Jurriaan plans to become a group leader in the field of embryonic development and embryonic stem cells, but with a focus on cellular structure. The main focus will be on exploring the role of compartmentalization of components into subcellular compartments in cellular decision making.
LINK to the the paper