[Heterochromatin compartments and gene silencing: human hematopoietic differentiation as a model study]

Abstract

In order to accomplish its differentiation program, the nucleus of a multipotent cell must be sequentially reprogrammed to acquire and maintain new gene expression patterns. When a stem cell is committed to differentiate towards a given lineage, global genome reprogramming involves both repression of non-affiliated genes and selective activation of genes involved in the establishment of the lineage. Accumulating evidence indicates that lineage specific gene expression is determined not only by the availability of specific transcription factors, but also by epigenetic modifications including both local modifications of DNA and chromatin structure, as well as global topological changes in chromosomes and genes positioning in the nucleus. Combined, these different levels of gene regulation allow for fine controls that integrate environmental and intracellular signals to establish appropriate gene expression programs, and hence ultimately determine the identity of the cell. Therefore, epigenetic modifications most likely precede gene activation and play a critical role in the choices of a stem cell to continue to self-renew or to differentiate. However, the cause-effect relationship between chromatin structure, nuclear architecture and cell-fate decisions is still a matter of debate. The pericentromeric heterochromatin compartment will be presented as one of the best studied examples to understand the impact of and positioning of a gene on its transcription. We will set the influence of heterochromatin compartments in the context of hematopoietic differentiation of human multipotent progenitors.