MoE Key Laboratory of Developmental Genetics and Neuropsychiatric Diseases, Bio-X Institutes, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240 Shanghai, PR China.
Dev Biol. 2013 Jul 15;379(2):167-81. doi: 10.1016/j.ydbio.2013.04.015. Epub 2013 Apr 24.
The Drosophila ovarian germline stem cells (GSCs) constantly experience self-renewal and differentiation, ensuring the female fertility throughout life. The balance between GSC self-renewal and differentiation is exquisitely regulated by the stem cell niche, the stem cells themselves and systemic factors. Increasing evidence has shown that the GSC regulation also involves epigenetic mechanisms including chromatin remodeling and histone modification. Here, we find that dBre1, an E3 ubiquitin ligase, functions in controlling GSC self-renewal and germ cell differentiation via distinct mechanisms. Removal or knock down of dBre1 function in the germline or somatic niche cell lineage leads to a gradual GSC loss and disruption of H3K4 trimethylation in the Drosophila ovary. Further studies suggest that the defective GSC maintenance is attributable to compromised BMP signaling emitted from the stem cell niche and impaired adhesion of GSCs to their niche. On the other hand, dBre1-RNAi expression in escort cells causes a loss of H3K4 trimethylation and accumulation of spectrosome-containing single germ cells in the germarium. Reducing dpp or dally levels suppresses the germ cell differentiation defects, indicating that dBre1 limits BMP signaling activities for the differentiation control. Strikingly, all phenotypes observed in dBre1 mutant ovaries can be mimicked by RNAi-based reduced expression of dSet1, a Drosophila H3K4 trimethylase. Moreover, genetic studies favor that dBre1 interacts with dSet1 in controlling GSC maintenance and germ cell differentiation. Taken together, we identify a dBre1/dSet1-dependent pathway for the H3K4 methylation involved in the cell fate regulation in the Drosophila ovary.
果蝇卵巢生殖干细胞（GSCs）不断经历自我更新和分化，以确保雌性终生的生育能力。GSC 自我更新和分化之间的平衡是由干细胞龛、干细胞本身和全身因素精细调节的。越来越多的证据表明，GSC 的调节还涉及表观遗传机制，包括染色质重塑和组蛋白修饰。在这里，我们发现 E3 泛素连接酶 dBre1 通过不同的机制在控制 GSC 自我更新和生殖细胞分化方面发挥作用。在生殖系或体细胞龛细胞谱系中去除或敲低 dBre1 功能会导致 GSC 逐渐丢失和果蝇卵巢中 H3K4 三甲基化的破坏。进一步的研究表明，GSC 维持的缺陷归因于来自干细胞龛的 BMP 信号的受损和 GSCs 与其龛的黏附受损。另一方面，在 escort 细胞中表达 dBre1-RNAi 会导致 H3K4 三甲基化丢失和生殖原细胞中含有 spectrosome 的单个生殖细胞的积累。降低 dpp 或 dally 水平可抑制生殖细胞分化缺陷，表明 dBre1 限制了 BMP 信号活性以控制分化。引人注目的是，在 dBre1 突变体卵巢中观察到的所有表型都可以通过基于 RNAi 的 dSet1 表达减少来模拟，dSet1 是一种果蝇 H3K4 三甲基化酶。此外，遗传研究表明，dBre1 与 dSet1 相互作用，共同控制 GSC 的维持和生殖细胞的分化。总之，我们确定了一个依赖于 dBre1/dSet1 的途径，该途径涉及 H3K4 甲基化，参与了果蝇卵巢中的细胞命运调控。
