The Asymmetry in Timing of DNA Replication Initiation in the Male Drosophila Germline

Many adult stem cells undergo asymmetric cell division (ACD) to produce both a self-renewing stem cell and a differentiating daughter cell. Stem cell ACD is crucial for maintaining tissue homeostasis and loss of asymmetric division is associated with both degenerative aging related diseases and cancers. A model system for studying stem cell ACD is the male Drosophila Germline Stem Cell (GSC). One key intrinsic factor underlying this asymmetric division in GSCs is the asymmetric segregation of canonical (old) and newly synthesized (new) histones: old histones are retained by the GSC and new histones are selectively segregated to the differentiating Gonialblast (GB) cell. While in theory asymmetric histone segregation could regulate the differential acquisition of new cell fates or processes, the precise mechanisms of how asymmetric histone inheritance regulates ACD is not understood. Here we show that during mitosis the old and new histone enriched sister chromatids show dramatically different properties as the new histone enriched sister chromatids fail to fully condense during mitosis and decondense more rapidly in telophase. The difference in mitotic condensation of sister chromatids is upstream of differences in timing of entry into the next cell cycle, where the GB proceeds into DNA replication before the GSC does. Under conditions that randomize histone inheritance, DNA replication initiation timing is randomized between the daughter cells. Furthermore, conditions that eliminate differential condensation/compaction of sister chromatids abolish DNA replication entry asymmetries. Together, these studies provide evidence that asymmetric histone inheritance induced differential mitotic chromatin compaction plays a role in DNA replication initiation timing, demonstrating a clear downstream effect of asymmetric histone inheritance