Abstract
SETDB1, a histone H3 lysine 9 (H3K9) methyltransferase, is crucial in meiosis and embryo development. This study aimed to investigate whether SETDB1 was associated with spermatogonial stem cells (SSC) homeostasis. We found that knockdown of Setdb1 impaired cell proliferation, led to an increase in reactive oxygen species (ROS) level through NADPH oxidase, and Setdb1 deficiency activated ROS downstream signaling pathways, including JNK and p38 MAPK, which possibly contributed to SSC apoptosis. Melatonin scavenged ROS and rescued the phenotype of Setdb1 KD. In addition, we demonstrated that SETDB1 regulated NADPH oxidase 4 (Nox4) and E2F1. Therefore, this study uncovers the new roles of SETDB1 in mediating intracellular ROS homeostasis for the survival of SSC.
Highlights
Male fertility depends on spermatogenesis, by which the haploid spermatozoa generate in the testes
We found that SETDB1 repressed expression of NADPH oxidase 4 (Nox4) and E2F Transcription Factor 1 (E2F1) and mediated reactive oxygen species (ROS) levels
We found that Setdb1 KD induced accumulation of ROS and upregulation of Nox3, Nox4, p22phox, and E2F1
Summary
Male fertility depends on spermatogenesis, by which the haploid spermatozoa generate in the testes. This process starts with the mitosis of the spermatogonial stem cells (SSCs), followed by meiosis of spermatocytes. The haploid spermatids transform into spermatozoa (KanatsuShinohara and Shinohara, 2013). This highly organized process of spermatogenesis requires timely coordinated gene expression that is regulated at the transcriptional and post-transcription levels (McSwiggin and O’Doherty, 2018). Setdb depletion induced SSC apoptosis through upregulating apoptotic inducers and downregulating apoptotic suppressors, and upregulating cytochrome c oxidase subunit IV isoform 2 (Cox4i2) through decreasing H3K9me (An et al, 2014). The up-regulation of COX4i2 is associated with elevated mitochondria-produced reactive oxygen species (ROS) (Singh et al, 2009)
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