RNA‐methyltransferase Nsun5 controls the maternal‐to‐zygotic transition by regulating maternal mRNA stability

Abstract

Background RNA modification‐induced ovarian dysgenesis appears to be necessary for ovary development. However, how m 5 C (5‐methylcytosine)‐coordinating modificatory transcripts are dynamically regulated during oogenesis, and ovarian development is unknown. The purpose of this study was to determine whether NOP2/Sun RNA methyltransferase 5 (Nsun5) deletion leads to suppression of ovarian function and arrest of embryonic development. The regulation of mRNA decay and stability by m 5 C modification is essential at multiple stages during the maternal‐to‐zygotic (MZT) transition. Methods Mouse ovaries and oocytes with Nsun5 KO and the KGN cell line were subjected to m 5 C identification, alternative splicing analysis and protein expression. BS‐m 5 C‐seq, real‐time polymerase chain reaction, Western blot, immunofluorescence and actinomycin D treatment assays were used. In particular, BS‐m 5 C‐seq revealed a dynamic pattern of m 5 C sites and genes in the ovaries between Nsun5 KO and WT mice at the 2‐month and 6‐month stages. Diverse bioinformatic tools were employed to identify target genes for Nsun5. Results Here, a maternal mRNA stability study showed that deletion of the m 5 C methyltransferase Nsun5 obstructs follicular development and ovarian function, which leads directly to inhibition of embryogenesis and embryo development. Dynamic analysis of m 5 C revealed that the level of m 5 C decreased in a time‐dependent manner after Nsun5 knockout. Regarding the molecular mechanism, we found that Nsun5 deficiency caused a m 5 C decline in the exon and 3′UTR regions that influenced the translation efficiency of Mitotic arrest deficient 2 like 2 (MAD2L2) and Growth differentiation factor 9 (GDF9) in the ovary. Mechanistic investigation of alternative splicing indicated that Nsun5 KO triggers aberrant events in the exon region of Brd8 . Conclusions Nsun5 loss arrests follicular genesis and development in ovarian aging, indicating that Nsun5/m 5 C‐regulated maternal mRNA stabilization is essential for MZT transition.

m6A and m5C modification of GPX4 facilitates anticancer immunity via STING activation

“…As a famous m6A “reader”, IGF2BP2 was confirmed to enhance mRNA stability and translation through its recognition of m6A modifications, and involve in the occurrence and development of various malignancies [ 47 ]. NSUN5 is one of the classical m5C methyltransferase, and it was reported to control the maternal-to-zygotic transition by regulating the translation efficiency of MAD2L2 and GDF9 in an m5C-dependent manner [ 48 ]. Strikingly, MeRIP-qPCR and RNA-stability assays also indicated that GPX4 was directly regulated by RBM15B- and IGFBP2 - mediated m6A modification and NSUN5-mediated m5C modification.…”

Theje ne sais quoiof 5-methylcytosine in messenger RNA

“…The extent of this m 5 C site upswell increased during evolution; higher animals gained many NSUN2-mediated at mRNA 5′ ends, whereas humans were unique in acquiring thousands of NSUN6-mediated sites across the CDS and UTR regions ( Liu et al 2022 ). NSUN5 sites were also present in data from human oocytes ( Liu et al 2023 ), and in mice, NSUN5 was shown to be involved in oocyte function through mRNA modification ( Ding et al 2022 ).…”

Ovarian aging: energy metabolism of oocytes

“…[203][204][205][206]. Additionally, RNA epitranscriptomes significantly impact oocyte quality [207][208][209][210][211][212][213]. The epigenome of oocytes changes with age, potentially contributing to the decline in oocyte quality associated with aging [206,[214][215][216][217][218].…”