Abstract：
Meiosis is a specialized cell division process that generates gametes for sexual reproduction. However, the factors and underlying mechanisms involving meiotic progression remain largely unknown, especially in humans. Here, it is first showed that HSF5 is associated with human spermatogenesis. Patients with a pathogenic variant of HSF5 are completely infertile. Testicular histologic findings in the patients reveal rare postmeiotic germ cells resulting from meiotic prophase I arrest. Hsf5 knockout (KO) mice confirms that the loss of HSF5 causes defects in meiotic recombination, crossover formation, sex chromosome synapsis, and sex chromosome inactivation (MSCI), which may contribute to spermatocyte arrest at the late pachytene stage. Importantly, spermatogenic arrest can be rescued by compensatory HSF5 adeno-associated virus injection into KO mouse testes. Mechanistically, integrated analysis of RNA sequencing and chromatin immunoprecipitation sequencing data revealed that HSF5 predominantly binds to promoters of key genes involved in crossover formation (e.g., HFM1, MSH5 and MLH3), synapsis (e.g., SYCP1, SYCP2 and SYCE3), recombination (TEX15), and MSCI (MDC1) and further regulates their transcription during meiotic progression. Taken together, the study demonstrates that HSF5 modulates the transcriptome to ensure meiotic progression in humans and mice. These findings will aid in genetic diagnosis of and potential treatments for male infertility.
摘要：
减数分裂是产生用于有性生殖的配子的专门的细胞分裂过程。然而,涉及减数分裂进展的因素和潜在机制仍然未知，尤其是在人类中。这里,首先表明HSF5与人类精子发生有关。具有HSF5致病变体的患者完全不育。患者的睾丸组织学发现显示，减数分裂前期I期停滞导致罕见的减数分裂后生殖细胞。Hsf5敲除（KO）小鼠证实，HSF5的缺失导致减数分裂重组的缺陷，交叉形成，性染色体突触，和性染色体失活（MSCI），这可能有助于精母细胞在粗线期晚期停滞。重要的是,通过将HSF5腺相关病毒代偿性注射入KO小鼠睾丸，可以挽救生精停滞。机械上,RNA测序和染色质免疫沉淀测序数据的综合分析显示，HSF5主要与参与交叉形成的关键基因的启动子结合（例如，HFM1、MSH5和MLH3)，突触(例如，SYCP1、SYCP2和SYCE3），重组(TEX15)，和MSCI（MDC1），并在减数分裂过程中进一步调节其转录。一起来看,该研究表明，HSF5调节转录组，以确保人和小鼠的减数分裂进程。这些发现将有助于男性不育的遗传诊断和潜在治疗。
