Geneviève Almouzni

Chromatin Dynamics

Geneviève Almouzni Chromatin dynamics, Epigenetics, Develoment, Genome stability, Histone chaperonnes

Development & Epigenesis Function of nucleosome assembly pathways specifying the choice of histone variant (ex role of H3.3 variant for Xenopus development, fig. 1) and mechanisms involved in the establishment of chromatin domains (ex centromeric domains in mouse cells)

Epigenetics Characterization of molecular mechanisms that establish and maintain specific chromatin domains defined by epigenetic parameters (ex pericentric domains in mouse cells fig. 2)

Chromatin organization in the nucleus of each cell provides a dynamic repertoire of information, beyond that encoded genetically. Regulation of this organization contributes to genome function and stability, with a major impact on cell fate. Our team investigates how chromatin organization is established, propagated, maintained, and altered during development and in response to environmental cues. Errors in the generation and inheritance of chromatin states can dysregulate essential genome functions, resulting in pathologies such as cancer.

Our objective is to decipher the mechanisms controlling chromatin dynamics, both at the level of nucleosome formation and at the scale of higher-order organization in the nucleus (Fig 1). We focus on challenges in physiological contexts such as replication, repair, cell cycle, development and cancer. Our 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. Our approach utilizes tools and model systems (e.g. Xenopus, mouse) that combine biochemistry, cell biology, developmental biology, epigenomics and advanced single molecule and single cell technologies.

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.

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.





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