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DNMT1-mediated lncRNA IFFD controls the follicular development via targeting GLI1 by sponging miR-370

Cell Death & Differentiation volume 30, pages 576–588 (2023)Cite this article

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Abstract

DNA methylation and long noncoding RNAs (lncRNAs) exhibit an indispensable role in follicular development. However, the specific mechanisms regarding lncRNAs mediated by DNA methylation in follicular development remain unclearly. In this study, we found that inhibiting the expression of DNMT1 promoted granulosa cells (GCs) apoptosis to inhibit follicular development. A novel follicular development-associated lncRNA named inhibitory factor of follicular development (IFFD) was mediated by DNMT1 and showed to arrest follicular development by inhibiting GCs proliferation and estrogen (E2) secretion but promoting GCs apoptosis. Mechanistically, the deactivated Cas9-TET1 demonstrated that the hypomethylation in −1261/−1254 region of IFFD promoted the transcription of IFFD by recruiting SP1. IFFD induced the expression of GLI family zinc finger 1 through competitive binding miR-370, thereby up-regulating the expression of CASP3 to promote GCs apoptosis, as well as downregulating the expressions of PCNA and CYP19A1 to inhibit GCs proliferation and E2 secretion. Collectively, DNMT1-mediated IFFD might be a novel target for the regulation of follicular development.

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Fig. 1: DNMT1 regulates the proliferation and apoptosis of GCs.
Fig. 2: DNMT1-mediated the expression of IFFD as ceRNA for miR370-GLI1 in GCs.
Fig. 3: IFFD as ceRNA for miR-370-GLI1 regulates the proliferation and apoptosis of GCs.
Fig. 4: DNMT1 blocks the binding of SP1 to inhibit the transcription of IFFD.
Fig. 5: IFFD as ceRNA for miR-370-GLI1 regulates follicular development in pigs.
Fig. 6: IFFD as ceRNA for miR-370-Gli1 controls follicular development in mice.

Data availability

The RNA-seq data supporting the results of this study have been deposited in the NCBI BioProject database under accession number PRJNA906921.

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Acknowledgements

This project was supported by the earmarked fund for China Agriculture Research System (CARS-35), the National Natural Science Foundation of China (32072694), the Guangdong Basic and Applied Basic Research Foundation (2021A1515012396), and the Science and Technology Project of Guangzhou (202002030071).

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  1. Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China

    Xiaofeng Zhou, Yingting He, Xiangchun Pan, Hongyan Quan, Bo He, Yongguang Li, Guofeng Bai, Nian Li, Zhe Zhang, Hao Zhang, Jiaqi Li & Xiaolong Yuan

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Contributions

XZ, ZZ, HZ, JL, and XY conceived the study. XZ, YH, GB, HQ, and YL conducted in vivo experiments. XZ, YH, BH, and NL conducted in vitro experiments. XZ and XP conducted the RNA-seq data analysis. XZ summarized results and wrote the manuscript.

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Correspondence to Jiaqi Li or Xiaolong Yuan.

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All experiments were conducted with strict reference to the Regulations for Administration of Affairs Concerning Experimental Animals, and approved by the Animal Care and Use Committee of South China Agricultural University with approval number: SYXK 2019-0136.

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Zhou, X., He, Y., Pan, X. et al. DNMT1-mediated lncRNA IFFD controls the follicular development via targeting GLI1 by sponging miR-370. Cell Death Differ 30, 576–588 (2023). https://doi.org/10.1038/s41418-022-01103-y

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