Epigenome plasticity during cellular differentiation

Abstract

Tight control of gene expression is crucial to govern cell function and identity at any developmental stage. Epigenetic modifications of chromatin have emerged as important determinants for chromatin structure and gene expression. The aim of this work was to test the hypothesis that epigenetic mechanisms contribute to the establishment and maintenance of cell type specific gene expression patterns and to delimiting the developmental potential of somatic cells. Towards this goal we defined genome-wide targets of epigenetic reprogramming during neuronal differentiation of mouse embryonic stem cells. DNA methylation, which is a potent and stable repressive modification, is increasing during differentiation of embryonic stem cells into neurons. Many de novo methylation targets encode pluripotency-associated and germline specific genes and only few appear to be specific for alternative lineages. Polycomb-mediated repression, a distinct epigenetic repression pathway, was previously shown to be essential for embryonic patterning and maintaining developmental potential in stem cells. Unlike DNA methylation, Polycomb targets are very dynamic during neuronal differentiation. Repression is resolved at activated genes while novel targets appear at both the multipotential neuronal progenitor state and the terminally differentiated neuron state. As in stem cells, many Polycomb targets in neuronal progenitor cells will be activated upon further differentiation. Polycomb could therefore serve as a general safe-guard system for genes that can be activated at later stages but need to be tightly controlled to avoid precocious and uncontrolled cell fate changes. In summary, there are at least two distinct epigenetic modes of repression, which nonetheless might crosstalk for target specification. Stable repression of the pluripotency program is conferred by DNA methylation. In turn, Polycomb mediates a more transient repression mechanism with cell type and developmental stage specific targets. Together, this argues that epigenetic mechanisms contribute to cellular differentiation and development via stabilizing gene expression programs initiated by transcription factors. Hence, epigenetic mechanisms could be viewed as additional regulatory layer for balancing gene regulation in order to confer robustness to cellular states and gene expression programs rather than as key drivers for setting up such cell type specific gene expression patterns.