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Abstract
Chromatin structure and its organization contributes to the proper regulation and timing of DNA replication. Yet, the precise mechanism by which chromatin contributes to DNA replication remains incompletely understood. This is particularly true for cell types that rely on polyploidization as a developmental strategy for growth and high biosynthetic capacity. During Drosophila larval development, cells of the salivary gland undergo endoreplication, repetitive rounds of DNA synthesis without intervening cell division, resulting in ploidy values of ~1350C. S phase of these endocycles displays a reproducible pattern of early and late replicating regions of the genome resulting from the activity of the same replication initiation factors that are used in diploid cells. However, unlike diploid cells, the latest replicating regions of polyploid salivary gland genomes, composed primarily of pericentric heterochromatic enriched in H3K9 methylation, are not replicated each endocycle, resulting in under-replicated domains with reduced ploidy. Here, we employ a histone gene replacement strategy in Drosophila to demonstrate that mutation of a histone residue important for heterochromatin organization and function (H3K9) but not mutation of a histone residue important for euchromatin function (H4K16), disrupts proper endoreplication in Drosophila salivary gland polyploid genomes thereby leading to DNA copy gain in pericentric heterochromatin. These findings reveal that H3K9 is necessary for normal levels of under-replication of pericentric heterochromatin and suggest that under-replication at pericentric heterochromatin is mediated through H3K9 methylation.
Highlights
Proper genome duplication is essential for normal development and tissue homeostasis
We used our histone gene replacement platform to generate H3K9R and H4K16R mutant larvae and determine whether replication-dependent H3K9 and H4K16 are necessary for endoreplication in the Drosophila salivary gland
We included in our analysis replication-dependent H3K9 and H4K16 in Drosophila salivary gland endoreplication
Summary
Proper genome duplication is essential for normal development and tissue homeostasis. Genome duplication and cell proliferation occur via canonical G1→S→G2→M cell cycles in which origins of replication are specified during G1 phase, DNA replication occurs during S phase and chromosome segregation and cell division occur during M phase [1]. Endopolyploidy is a common feature of normal development in both plants and animals, polyploidy can result from mis-regulation of the canonical diploid cell cycle and is commonly associated with human disease [4,5]. Determining mechanisms that regulate polyploid cell cycles is important for understanding both normal and pathological development. The giant polytene chromosomes of the polyploid cells of the Drosophila larval salivary gland have long served as a model experimental tissue for understanding endoreplication [8,9]. During late embryonic and larval development, approximately ten endoreplication cycles yield a final ploidy of ~1350C in salivary gland cells [9,10]
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