Chromatin Dynamics

Chromatin organization in the nucleus provides a large repertoire of information in addition to that encoded genetically. Understanding how this information is established and possibly inherited through cell division is a challenge for the field. A key question is how histones, the major protein components of chromatin, as particular variants or post-translationally modified forms, can mark functional regions of the genome.

Our team is interested in understanding how chromatin organization is established, propagated, maintained, and changed during development and in response to environmental cues. Errors in these processes can lead to mis-regulation of genome functions and pathological outcomes, such as cancer.

Figure 1 : Chromatin assembly during several DNA transactions in physiological contexts. To form the basic building block of chromatin, the nucleosome, the DNA helix wraps around a central complex of histone proteins. This assembly uses both new histone deposition and recycling of parental histones from pre-existing nucleosomes.

Our general objective has been to dissect the mechanisms of chromatin assembly, from the basic structural unit, the nucleosome, up to higher-order structures in the nucleus (Fig. 1). We have characterized key chaperones involved in nucleosome assembly and defined the dynamics of new histone incorporation in chromatin. Our findings have shed light on the fundamental issues of the dynamics, fate, and inheritance of histones, with their specific marks typical of particular chromatin domains.

Our working hypothesis is that histone chaperones function in an ‘assembly line’ with specificity for individual histone variants to mark defined regions of the genome. Remarkably, we have found that misregulation of specific histone chaperones is a common feature of aggressive breast cancers.

Our plan is to analyze the regulatory pathways that target histone chaperones and variants to control the assembly line and its connecting network.

Figure 2. The importance of H3 variants and their chaperones during various stages of mouse development. The fusion of two highly differentiated gametes (A,B) into a zygote (C). This cell acquires totipotency and starts dividing (D,E), giving rise to daughter cells that will specialize progressively (F). The diverse cell lineages they establish will differentiate into the array of tissues in the adult organism (G,I). Among these lineages, primary germ cells (PGCs) undergo reprogramming to establish the germline of the adult (H), allowing it to produce either male or female gametes similar to those it originated from. H3 variants and their chaperones have been shown to contribute to the regulation of these processes (green or red arrows). For some, their contribution to developmental progression remains elusive (orange). From Filipescu D. et al., 2013.

Our specific approach to understanding all the in vivo functions of chromatin complexes is based on tools and model systems (e.g. Xenopus, mouse) that combine biochemistry, cell biology, and developmental biology (Fig. 2). We examine specific nuclear domains: non-coding centromeric heterochromatic regions, which are of major importance for chromosome segregation.

Together these studies should ultimately help in the development of medical applications of relevance for cancer.