果蝇组蛋白甲基转移酶SET1在调节男性种系干细胞维持和分化时协调多个信号通路
The Drosophila histone methyltransferase SET1 coordinates multiple signaling pathways in regulating male germline stem cell maintenance and differentiation
影响因子:3.60000
分区:生物学2区 / 发育生物学2区
发表日期:2024 Aug 01
作者:
Velinda Vidaurre, Annabelle Song, Taibo Li, Wai Lim Ku, Keji Zhao, Jiang Qian, Xin Chen
摘要
许多组织特异性的成年干细胞谱系在增殖和分化之间保持平衡。在这里，我们研究了H3K4ME3甲基转移酶SET1如何调节果蝇中的早期男性生殖细胞。 SET1的早期种系特异性敲低会导致暂时性的缺陷，这是由于生殖细胞丧失并发展为人口过多的早期生殖细胞。这些种系缺陷也会影响小众结构和囊肿干细胞谱系非自治。此外，野生型SET1（而不是催化无效的SET1）营救了SET1敲低表型，突出了SET1的甲基转移酶活性的功能重要性。此外，RNA测序实验揭示了关键信号通路成分，例如JAK-STAT途径基因STAT92E和BMP途径基因MAD，它们在SET1敲低时被上调。遗传相互作用分析支持SET1和JAK-STAT或BMP途径之间的功能关系，因为STAT92E和MAD突变都抑制了SET1敲低表型。这些发现增强了我们对成年干细胞谱系增殖与分化之间平衡的理解。在抑制组蛋白甲基转移酶时，生殖细胞损失的表型随后是过度增殖的，这也引起了人们对在癌症治疗中使用其抑制剂的担忧。
Abstract
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 progressive 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 methyltransferase activity of Set1. Further, RNA-sequencing experiments reveal key signaling pathway components, such as the JAK-STAT pathway gene Stat92E and the BMP pathway gene Mad, which 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 phenotype of germ cell loss followed by over-proliferation when inhibiting a histone methyltransferase also raises concerns about using their inhibitors in cancer therapy.