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Theranostics 2024; 14(6):2345-2366. doi:10.7150/thno.95164 This issue Cite

Research Paper

HDAC6-dependent deacetylation of NGF dictates its ubiquitination and maintains primordial follicle dormancy

Tuo Zhang^1,2,3,4,5,6#, Yuntong Tong^1#, Rengguang Zhu⁷, Yaoyun Liang⁴, Jixian Zhang¹, Chujiao Hu⁷, Meina He^1,6, Zhu Hu⁴, Zhiyi Shen¹, Jin Niu², Jingjing Zhang¹, Yuanyuan Yu¹, Bangming Jin¹, Shan Lei¹, Zhirui Zeng¹, Yingmin Wu¹, Zengmei Cheng⁴, Ziwen Xiao⁵, Bing Guo³, Shuyun Zhao^4✉, Guoqiang Xu^1✉, Wei Pan^2✉, Tengxiang Chen^1,3,6✉

1. Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550009, China.
2. Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550009, China.
3. Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, 550009, China.
4. Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, Guiyang, Guizhou, 550009, China.
5. Department of Obstetrics and Gynecology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550009, China.
6. Guizhou Institute of Precision Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550009, China.
7. College of Pharmacy, Guizhou Medical University, Guizhou Medical University, Guiyang, Guizhou, 550009, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Tengxiang Chen, Email: txchedu.cn; Wei Pan, Email: 313831139com; Guoqiang Xu, Email: 1737049021com; Shuyun Zhao, E-mail: Zhaosy68com; Department of Physiology, College of Basic Medicine, Guizhou Medical University, Ankang Road, Anshun, Guizhou, China. More

Abstract

Rationale: Primordial follicles are limited in number and cannot be regenerated, dormant primordial follicles cannot be reversed once they enter a growth state. Therefore, the length of the female reproductive lifespan depends on the orderly progression and selective activation of primordial follicles, the mechanism of which remains unclear.

Methods: We used human ovarian cortical biopsy specimens, granulosa cells from diminished ovarian reserve (DOR) patients, Hdac6-overexpressing transgenic mouse model, and RNA sequencing to analyze the crucial roles of histone deacetylase 6 (HDAC6) in fertility preservation and primordial follicle activation.

Results: In the present study, we found that HDAC6 was highly expressed in most dormant primordial follicles. The HDAC6 expression was reduced accompanying reproductive senescence in human and mouse ovaries. Overexpression of Hdac6 delayed the rate of primordial follicle activation, thereby prolonging the mouse reproductive lifespan. Short-term inhibition of HDAC6 promoted primordial follicle activation and follicular development in humans and mice. Mechanism studies revealed that HDAC6 directly interacted with NGF, reducing acetylation modification of NGF and thereby accelerating its ubiquitination degradation. Consequently, the reduced NGF protein level maintained the dormancy of primordial follicles.

Conclusions: The physiological significance of the high expression of HDAC6 in most primordial follicles is to reduce NGF expression and prevent primordial follicle activation to maintain female fertility. Reduced HDAC6 expression increases NGF expression in primordial follicles, activating their development and contributing to reproduction. Our study provides a clinical reference value for fertility preservation.

Keywords: HDAC6, NGF, ovary, primordial follicle, fertility preservation

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