JMJD1C, a JmjC Domain-Containing Protein, Is Required for Long-Term Maintenance of Male Germ Cells in Mice1

Abstract

JmjC domain-containing proteins are a class of enzymes responsible for histone demethylation. Previous studies revealed that the JmjC domain-containing protein KDM3A possesses intrinsic demethylase activity toward lysine 9 of histone H3 and plays essential roles in spermiogenesis. In contrast, the biological roles of JMJD1C, a KDM3A homolog in mice, are largely unknown. Here we present the crucial role of JMJD1C in male gametogenesis. Jmjd1c-deficient males became infertile due to the progressive reduction of germ cells after 3 mo of age. Importantly, Jmjd1c-deficient testes frequently contained abnormal tubules lacking developmentally immature germ cells. JMJD1C is most abundantly expressed in undifferentiated spermatogonia in mouse testis. The numbers of ZBTB16-positive spermatogonia and apoptotic germ cells in Jmjd1c-deficient testes decreased and increased in an age-dependent manner, respectively. Our studies demonstrated that JMJD1C contributes to the long-term maintenance of the male germ line.

Pluripotency Transcription Factor Oct4 Mediates Stepwise Nucleosome Demethylation and Depletion

“…Recent work suggests that Jmjd1c associates with the transcription factor Nanog (56), but evidence for a functional role as a Nanog cofactor is lacking. Jmjd1c is important for maintenance of spermatogonial germ cells (57), and rare germ line Jmjd1c variants are associated with certain germ cell tumors (58). In addition, Jmjd1c is a downstream Oct4 target (59), suggesting a possible regulatory loop.…”

MLL-AF9– and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C

“…First identified in a yeast 2-hybrid assay as thyroid receptor-interacting protein (TRIP8) (31), JMJD1C has been shown to be a coactivator for the androgen receptor (32). JMJD1C is required in male gametogenesis (33) and has been shown to represses neural differentiation of human embryonic stem cells by maintaining miR-302 expression (34). Germline variants of JMJD1C are associated with increased risk of developing intracranial germ cell tumors (35), and recently, shRNA approaches demonstrated a requirement for JMJD1C in leukemia maintenance (36).…”

Expression pattern of JMJD1C in oocytes and its impact on early embryonic development

“…JMJD1A is an essential regulator in the development of embryonic stem cells (Loh et al, 2007). Kuroki et al (2013) found that JMJD1C plays an important role in mouse spermatogenesis using JMJD1C knockout male mice model. They showed gradual reduction in germ cells at 3 months, leading to infertility and testicular fine tubule malformation and failed to produce normal primordial germ cells.…”

“…Studies have shown that in meiosis, H3K9me1 and H3K9me2 show temporary dynamic changes and have different characteristics in male and female germ cells (Tachibana et al, 2007). Additionally, studies have shown that in JMJD1C knockout male mice, the number of germ cells gradually decreases with age leading to infertility, and that JMJD1C does not affect H3K9 methylation level of the whole genome but only at specific sites and during specific stages (Kuroki et al, 2013). Therefore, our future research focus will be on the specific functions of JMJD1C in early embryonic development.…”