果蝇组蛋白甲基转移酶SET1在调控雄性生殖干细胞维持与分化中的多重信号通路协调作用

The Drosophila histone methyltransferase SET1 coordinates multiple signaling pathways in regulating male germline stem cell maintenance and differentiation

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DEVELOPMENT

影响因子:3.6

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

DOI: 10.1242/dev.202729

摘要

许多组织特异性的成人干细胞系在增殖与分化之间维持平衡。本文研究H3K4me3甲基转移酶Set1如何调控果蝇早期雄性生殖细胞。对Set1的早期阶段生殖系特异性敲低导致时间性逐步的缺陷，表现为生殖细胞的丢失，最终形成早期生殖细胞过度增殖。这些生殖系缺陷还影响细胞环境架构和囊胚干细胞谱系的非细胞自主性形成。此外，野生型Set1（而非催化活性失活的Set1）能拯救Set1敲低的表型，强调甲基转移酶活性的功能重要性。RNA测序分析发现，JAK-STAT信号通路的关键组分，如Stat92E，以及BMP通路的Mad，在Set1敲低后上调。遗传相互作用试验证实Set1与JAK-STAT或BMP通路具有功能关联，Stat92E和Mad突变均能抑制Set1敲低的表型。这些发现加深了我们对成人干细胞系中增殖与分化平衡的理解。抑制组蛋白甲基转移酶导致生殖细胞丢失后过度增殖的表型，也提示其在癌症治疗中抑制剂的潜在风险。

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.