| dc.description.abstract | Histones are essential for the structure and function of chromatin, serving as the basic units of chromatin packaging, thus exerting major influence over DNA organization and gene expression regulation. Additionally, histones contribute to the maintenance of genomic stability and DNA repair. Given the significant role of histones in all chromatin-related biology, it is crucial that histone levels are tightly regulated. Imbalances in histone levels can lead to defects in chromatin packaging, gene expression, and susceptibility to DNA damage.
In somatic cells, histones are stringently regulated. Canonical histones are predominantly synthesized in S-phase to ensure proper packaging of the newly replicated DNA. Additionally, 99% of histones are bound by chromatin and the 1% of soluble histones are always bound by histone chaperones. This prevents toxicity of overexpressed histones. Interestingly, in the rapidly dividing embryo, there is an abundance of maternally deposited histone proteins. Presumably the large pools of histones are required to supplement rapid DNA replication. However, the H3-H4 chaperone that maintains these large pools of H3-H4 in the early embryo is unknown. In somatic cells, H3-H4 chaperone NASP functions to store <1% of soluble histone pools.
Does NASP modulate large reservoirs of H3-H4 in the early embryo?
While there is sufficient evidence to support NASP’s role in storing the 1% of soluble H3-H4 levels in somatic cells, the question remains whether it can modulate histone pools (>99%) present in the early embryo. Given that NASP is embryonic lethal and is highly expressed in human and mouse embryonic stem cells, there is suitable rationale that it may function as a H3-H4 chaperone in the early embryo as well.
In this thesis, I establish that the Drosophila NASP homolog maintains the large pools of H3-H4 in the early embryo. Briefly, I observed that NASP null mutant is viable but is a maternal effect gene. Embryos laid by NASP mutant mothers have a reduced rate of hatching and show defects in early embryogenesis. Critically, soluble H3-H4 pools are depleted in embryos laid by NASP mutant mothers. This body of work provides evidence for NASP function as a storage for H3-H4 in the early embryo. | |
