Oocyte-Specific Knockout of Histone Lysine Demethylase KDM2a Compromises Fertility by Blocking the Development of Follicles and Oocytes

Xianrong Xiong; Xiaojian Zhang; Manzhen Yang; Yanjin Zhu; Hailing Yu; Xixi Fei; Fuko Mastuda; Daoliang Lan; Yan Xiong; Wei Fu; Shi Yin; Jian Li

doi:10.3390/ijms231912008

Oocyte-Specific Knockout of Histone Lysine Demethylase KDM2a Compromises Fertility by Blocking the Development of Follicles and Oocytes

Int J Mol Sci. 2022 Oct 9;23(19):12008. doi: 10.3390/ijms231912008.

Authors

Xianrong Xiong^{1

2}, Xiaojian Zhang³, Manzhen Yang², Yanjin Zhu², Hailing Yu¹, Xixi Fei¹, Fuko Mastuda⁴, Daoliang Lan¹, Yan Xiong¹, Wei Fu¹, Shi Yin¹, Jian Li^{1

2}

Affiliations

¹ Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China.
² Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China.
³ Center for Assisted Reproduction, Sichuan Academy of Medical Science, Sichuan Provincial People's Hospital, Chengdu 610072, China.
⁴ Laboratory of Theriogenology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.

Abstract

The methylation status of histones plays a crucial role in many cellular processes, including follicular and oocyte development. Lysine-specific demethylase 2a (KDM2a) has been reported to be closely associated with gametogenesis and reproductive performance, but the specific function and regulatory mechanism have been poorly characterized in vivo. We found KDM2a to be highly expressed in growing follicles and oocytes of mice in this study. To elucidate the physiological role of Kdm2a, the zona pellucida 3-Cre (Zp3-Cre)/LoxP system was used to generate an oocyte Kdm2a conditional knockout (Zp3-Cre; Kdm2a^flox/flox, termed Kdm2a cKO) model. Our results showed that the number of pups was reduced by approximately 50% in adult Kdm2a cKO female mice mating with wildtype males than that of the control (Kdm2a^flox/flox) group. To analyze the potential causes, the ovaries of Kdm2a cKO mice were subjected to histological examination, and results indicated an obvious difference in follicular development between Kdm2a cKO and control female mice and partial arrest at the primary antral follicle stage. The GVBD and matured rates of oocytes were also compromised after conditional knockout Kdm2a, and the morphological abnormal oocytes increased. Furthermore, the level of 17β-estradiol of Kdm2a cKO mice was only 60% of that in the counterparts, and hormone sensitivity decreased as the total number of ovulated and matured oocytes decreased after superovulation. After deletion of Kdm2a, the patterns of H3K36me2/3 in GVBD-stage oocytes were remarkedly changed. Transcriptome sequencing showed that the mRNA expression profiles in Kdm2a cKO oocytes were significantly different, and numerous differentially expressed genes were involved in pathways regulating follicular and oocyte development. Taken together, these results indicated that the oocyte-specific knockout Kdm2a gene led to female subfertility, suggesting the crucial role of Kdm2a in epigenetic modification and follicular and oocyte development.

Keywords: Kdm2a; epigenetic modification; folliculogenesis; oocyte; subfertility.

MeSH terms

Animals
Estradiol / metabolism
Female
Fertility / genetics
Histones* / metabolism
Jumonji Domain-Containing Histone Demethylases* / genetics
Lysine / metabolism
Male
Mice
Mice, Knockout
Oocytes / metabolism
RNA, Messenger / metabolism

Substances

Histones
RNA, Messenger
Estradiol
FBXL11 protein, mouse
Jumonji Domain-Containing Histone Demethylases
Lysine

Grants and funding

The study was supported by the Key Research and Development Program of Sichuan Provincial Science and Technology Program (2022YFS0058 & 2021YFN0121), the Fund of China Scholarship Council (No. 202008510085), and the Fundamental Research Funds for the Central Universities of Southwest Minzu University (No. 2021PTJS20).