Distinct Roles of NANOS1 and NANOS3 in the Cell Cycle and NANOS3-PUM1-FOXM1 Axis to Control G2/M Phase in a Human Primordial Germ Cell Model

Abstract

Nanos RNA-binding proteins are critical factors of germline development throughout the animal kingdom and their dysfunction causes infertility. During evolution, mammalian Nanos paralogues adopted divergent roles in germ cell biology. However, the molecular basis behind this divergence, such as their target mRNAs, remains poorly understood. Our RNA-sequencing analysis in a human primordial germ cell model‑TCam-2 cell line revealed distinct pools of genes involved in the cell cycle process downregulated upon NANOS1 and NANOS3 overexpression. We show that NANOS1 and NANOS3 proteins influence different stages of the cell cycle. Namely, NANOS1 is involved in the G1/S and NANOS3 in the G2/M phase transition. Many of their cell cycle targets are known infertility and cancer-germ cell genes. Moreover, NANOS3 in complex with RNA-binding protein PUM1 causes 3′UTR-mediated repression of FOXM1 mRNA encoding a transcription factor crucial for G2/M phase transition. Interestingly, while NANOS3 and PUM1 act as post-transcriptional repressors of FOXM1, FOXM1 potentially acts as a transcriptional activator of NANOS3, PUM1, and itself. Finally, by utilizing publicly available RNA-sequencing datasets, we show that the balance between FOXM1-NANOS3 and FOXM1-PUM1 expression levels is disrupted in testis cancer, suggesting a potential role in this disease.

Emerging Roles of NANOS RNA-Binding Proteins in Cancer

“…Moreover, it is a well-known oncogene. FOXM1 was shown to bind to the promoter of NANOS3 in a human germ cell model [ 54 ]. This study showed a mechanism in which NANOS3 expression is induced by FOXM1; in return, NANOS3 represses FOXM1 through 3’UTR of its mRNA.…”

Characterization of the In Vitro Cultured Ovarian Cells in the Asian Yellow Pond Turtle (Mauremys mutica)

“…To assess the reliability of the RNA-seqs data, we further determined the expression profiles of germline marker genes tdrd7 , nanos1 , klf5 , igtb1 , hsd17b4 and rad51 in a panel of tissues or cells, including testis, ovary, the cultured ovarian cells, liver, spleen and kidney, since these genes have been documented in many species [ 37 , 38 , 39 , 40 , 41 , 42 ]. As described above, the morphology of cells became more uniform from passage 20 ( Figure 1 C), therefore, the expression profile of these marker genes was examined using cells at passage 20.…”

The RNA-binding protein NANOS1 controls hippocampal synaptogenesis

“…NANOS proteins are also implicated in cancer, in connection with their capacity to control cell proliferation, differentiation and apoptosis. Moreover, alterations of NANOS 1, NANOS 2 or NANOS 3 expression levels correlate with tumorigenesis in a complex pattern [1,4,[9][10][11][12][13][14][15][16][17].…”