Histone H3 Threonine Phosphorylation Regulates Asymmetric Histone Inheritance in the Drosophila Male Germline

• Published in: Cell 2015-11, Vol.163 (4), p.920-933
• Main Authors: Xie, Jing, Wooten, Matthew, Tran, Vuong, Chen, Bi-Chang, Pozmanter, Caitlin, Simbolon, Christine, Betzig, Eric, Chen, Xin
• Format: Article
• Language: English
• Subjects: Animals; Drosophila melanogaster - cytology; Drosophila melanogaster - metabolism; Drosophila Proteins - chemistry; Drosophila Proteins - metabolism; Germ Cells - cytology; Germ Cells - metabolism; Histones - chemistry; Histones - metabolism; Male; Mitosis; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Spermatogenesis; Stem Cells - cytology; Stem Cells - metabolism; Testis - metabolism; Threonine - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.10.002

A long-standing question concerns how stem cells maintain their identity through multiple divisions. Previously, we reported that pre-existing and newly synthesized histone H3 are asymmetrically distributed during Drosophila male germline stem cell (GSC) asymmetric division. Here, we show that phosphorylation at threonine 3 of H3 (H3T3P) distinguishes pre-existing versus newly synthesized H3. Converting T3 to the unphosphorylatable residue alanine (H3T3A) or to the phosphomimetic aspartate (H3T3D) disrupts asymmetric H3 inheritance. Expression of H3T3A or H3T3D specifically in early-stage germline also leads to cellular defects, including GSC loss and germline tumors. Finally, compromising the activity of the H3T3 kinase Haspin enhances the H3T3A but suppresses the H3T3D phenotypes. These studies demonstrate that H3T3P distinguishes sister chromatids enriched with distinct pools of H3 in order to coordinate asymmetric segregation of “old” H3 into GSCs and that tight regulation of H3T3 phosphorylation is required for male germline activity. [Display omitted] •Pre-existing versus newly synthesized H3 are separable in prophase germline stem cell•H3 threonine 3 phosphorylation distinguishes pre-existing from newly synthesized H3•Both H3T3A and H3T3D mutations randomize H3 inheritance patterns•Reducing H3T3 kinase Haspin enhances the H3T3A but suppresses the H3T3D phenotypes A transient mitosis-specific phosphate modification on histone H3 distinguishes pre-existing and newly synthesized histones and is required for the asymmetric segregation of sister chromatids—one enriched with new histones and the other with old—during stem cell division.