许多组织特异性成体干细胞谱系维持增殖和分化之间的平衡。在这里，我们研究了 H3K4me3 甲基转移酶 Set1 如何调节果蝇的早期雄性生殖细胞。 set1 的早期种系特异性敲除会导致暂时进展的缺陷，由于生殖细胞丢失而产生并发育成数量过多的早期生殖细胞。这些种系缺陷也会非细胞自主地影响生态位结构和囊肿干细胞谱系。此外，野生型 Set1（而非催化失活的 Set1）挽救了 set1 敲低表型，凸显了 Set1 甲基转移酶活性的功能重要性。此外，RNA-seq 实验揭示了关键信号通路组件，例如 JAK-STAT 通路 stat92E 和 BMP 通路 mad 基因，这些基因在 set1 敲低后上调。遗传相互作用分析支持 set1 和 JAK-STAT 或 BMP 通路之间的功能关系，因为 stat92E 和 mad 突变都会抑制 set1 敲低表型。这些发现增强了我们对成体干细胞谱系增殖和分化之间平衡的理解。抑制组蛋白甲基转移酶时，生殖细胞损失，随后出现过度增殖表型，这也引起了人们对在癌症治疗中使用其抑制剂的担忧。© 2024。由 The Company of Biologies Ltd 出版。

Many tissue-specific adult stem cell lineages maintain a balance between proliferation and differentiation. Here, we study how the H3K4me3 methyltransferase, Set1, regulates early-stage male germ cells in Drosophila. Early-stage germline-specific knockdown of set1 results in temporally progressed defects, arising as germ cell loss and developing into overpopulated early-stage germ cells. These germline defects also impact the niche architecture and cyst stem cell lineage non-cell-autonomously. Additionally, wild-type Set1, but not the catalytically inactive Set1, rescues the set1 knockdown phenotypes, highlighting the functional importance of the methyl-transferase activity of Set1. Further, RNA-seq experiments reveal key signaling pathway components, such as the JAK-STAT pathway stat92E and the BMP pathway mad genes that are upregulated upon set1 knockdown. Genetic interaction assays support the functional relationships between set1 and JAK-STAT or BMP pathways, as both stat92E and mad mutations suppress the set1 knockdown phenotypes. These findings enhance our understanding of the balance between proliferation and differentiation in an adult stem cell lineage. The germ cell loss followed by over-proliferation phenotype when inhibiting a histone methyl-transferase also raise concerns about using their inhibitors in cancer therapy.© 2024. Published by The Company of Biologists Ltd.