Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
The Shine-Dalgarno Centre for RNA Innovation, The John Curtin School of Medical Research, The Australian National University, Acton, Australian Capital Territory 2601, Australia.
Genes Dev. 2024 Oct 16;38(17-20):866-886. doi: 10.1101/gad.351930.124.
Animal germline development and fertility rely on paralogs of general transcription factors that recruit RNA polymerase II to ensure cell type-specific gene expression. It remains unclear whether gene expression processes downstream from such paralog-based transcription is distinct from that of canonical RNA polymerase II genes. In , the testis-specific TBP-associated factors (tTAFs) activate over a thousand spermatocyte-specific gene promoters to enable meiosis and germ cell differentiation. Here, we show that efficient termination of tTAF-activated transcription relies on testis-specific paralogs of canonical polymerase-associated factor 1 complex (PAF1C) proteins, which form a testis-specific PAF1C (tPAF). Consequently, tPAF mutants show aberrant expression of hundreds of downstream genes due to read-in transcription. Furthermore, tPAF facilitates expression of Y-linked male fertility factor genes and thus serves to maintain spermatocyte-specific gene expression. Consistently, tPAF is required for the segregation of meiotic chromosomes and male fertility. Supported by comparative in vivo protein interaction assays, we provide a mechanistic model for the functional divergence of tPAF and the PAF1C and identify transcription termination as a developmentally regulated process required for germline-specific gene expression.
动物生殖细胞的发育和生育能力依赖于一般转录因子的同源物，这些同源物招募 RNA 聚合酶 II，以确保细胞类型特异性基因表达。目前尚不清楚基于这种同源物的转录下游的基因表达过程是否与规范的 RNA 聚合酶 II 基因的表达过程不同。在这项研究中，睾丸特异性 TBP 相关因子 (tTAFs) 激活超过一千个精母细胞特异性基因启动子，以实现减数分裂和生殖细胞分化。在这里，我们表明，tTAF 激活转录的有效终止依赖于规范的聚合酶相关因子 1 复合物 (PAF1C) 蛋白的睾丸特异性同源物，这些同源物形成了睾丸特异性 PAF1C (tPAF)。因此，tPAF 突变体由于读入转录而显示数百个下游基因的异常表达。此外，tPAF 促进了 Y 连锁雄性生育因子基因的表达，因此有助于维持精母细胞特异性基因表达。通过比较体内蛋白质相互作用测定，我们提供了 tPAF 和 PAF1C 功能分化的机制模型，并确定转录终止是生殖细胞特异性基因表达所需的发育调控过程。
