A central question in chromatin biology is how to both structurally organize the genome and mark specific regions with a choice of histone variants. Understanding how to establish and maintain, but also how to change chromatin states is a fundamental challenge. Although histone modifications have been studied intensively, less is known about mechanisms concerning histone variant placement. Histone chaperones are escort factors that regulate the supply, loading, eviction, and degradation of histone variants. They are key in the placement of histone variants at specific chromatin landmarks and bridge organization scales from the nucleosome to higher order structures. Indeed, selective chaperone-variant partnerships have been documented in multicellular organisms, yet recently, dosage imbalances occurring in natural and pathological contexts underline plasticity in these interactions. Considering the known changes in histone dosage during development, we aimed to re-evaluate chaperone function not as individual fixed modules, but rather as a dynamic circuitry that adapts to cellular needs during the cell cycle, DNA replication and repair, differentiation, development, and pathology.Our project CHROMatin ADaptation through Interactions with Chaperones in Time (ChromAdICT) has built on our proposed concept by which a partial interchangeability in chaperones and histone variants provides unique possibilities to respond to cellular demands during the cell cycle and during development. A control of these dynamics at distinct chromatin regions could thus contribute to not only establish and maintain functional domains, but also to a plasticity enabling to adapt properties locally. We thus explored how this balance in chromatin stability and plasticity could be tuned in distinct cell types depending on context. We explored the underlying mechanisms enabling adaptability to naturally as well as experimentally induced chaperone and variant dosage changes over time. Our dissection of how chaperone-histone complexes act as a coordinated team of chromatin architects enabled four complementary and interconnected achievements.
1.We engineered a toolbox for probing the chaperone-variant partnership nature and plasticity.
2. We assessed the dynamics of histone variants promoted by chaperones during DNA replication and damage assessing the fate of new and old histones.
3. We explored the Impact of the chaperone-histone partnership on functional chromosome landmarks – with a particular focus on centromeres, telomeres, heterochromatin, and DNA regulatory elements.
4. We evaluated the plasticity and adaptability of histone dynamics during differentiation and T cell commitment in mice and during development in Xenopus.
Taken together these results obtained within the project illustrate the importance of characterizing the relationships between histones and their dedicated chaperones, including their dosage and dynamics, to understand how these can impact on cell fate, survival and maintenance of chromatin marks supported by histone variants. Now these findings prove their importance for medical applications and have led to innovation strategies.
