LSD1 promotes the FSH responsive follicle formation by regulating autophagy and repressing Wt1 in the granulosa cells

Zijian Zhu ¹Meina He ²Tuo Zhang ³Ting Zhao ¹Shaogang Qin ¹Meng Gao ¹Wenji Wang ⁴Wenying Zheng ¹Ziqi Chen ¹Longping Liu ⁵Ming Hao ⁵Bo Zhou ¹Hua Zhang ¹Jianbin Wang ⁵Fengchao Wang ⁶Guoliang Xia ⁷Chao Wang¹

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作者信息

1. State Key Laboratory of Farm Animal Biotech Breeding,College of Biological Sciences,China Agricultural University,Beijing 100193,China
2. College of Basic Medicine,Guizhou Medical University,Guiyang 550025,China
3. Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases,Department of Physiology,College of Basic Medicine,Guizhou Medical University,Guiyang 550025,China
4. School of Life Sciences,Taizhou University,Taizhou 318000,China
5. School of Life Sciences,Tsinghua University,Beijing 100084,China
6. Transgenic Animal Center,National Institute of Biological Sciences,Beijing 102206,China
7. State Key Laboratory of Farm Animal Biotech Breeding,College of Biological Sciences,China Agricultural University,Beijing 100193,China;Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China,College of Life Science,Ningxia University,Yinchuan 750021,China
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Abstract

In a growing follicle,the survival and maturation of the oocyte largely depend on support from somatic cells to facilitate FSH-induced mutual signaling and chemical communication.Although apoptosis and autophagy in somatic cells are involved in the process of FSH-induced follicular development,the under-lying mechanisms require substantial study.According to our study,along with FSH-induced antral fol-licles(AFs)formation,both lysine-specific demethylase 1(LSD1)protein levels and autophagy increased simultaneously in granulosa cells(GCs)in a time-dependent manner,we therefore evaluated the impor-tance of LSD1 upon facilitating the formation of AFs correlated to autophagy in GCs.Conditional knockout of Lsd1 in GCs resulted in significantly decreased AF number and subfertility in females,accompanied by marked suppression of the autophagy in GCs.On the one hand,depletion of Lsd1 resulted in accumulation of Wilms tumor 1 homolog(WT1),at both the protein and mRNA levels,WT1 prevented the expression of FSH receptor(Fshr)in GCs and thus reduced the responsiveness of the secondary follicles to FSH induc-tion.On the other hand,depletion of LSD1 resulted in suppressed level of autophagy by upregulation of ATG16L2 in GCs.We finally approved that LSD1 contributed to these sequential activities in GCs through its H3K4me2 demethylase activity.Therefore,the importance of LSD1 in GCs is attributable to its roles in both accelerating autophagy and suppressing WT1 expression to ensure the responsiveness of GCs to FSH during AFs formation.

Key words

LSD1/Autophagy/H3K4me2/WT1/Follicle formation/Follicle stimulating hormone

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基金项目

National Key Research & Developmental Program of China(2022YFC2703803)

National Key Research & Developmental Program of China(2018YFC1003700)

National Key Research & Developmental Program of China(2018YFC1003801)

National Key Research & Developmental Program of China(2023YFD1300501)

National Natural Science Foundation of China(32071132)

National Natural Science Foundation of China(31872792)

National Natural Science Foundation of China(32270904)

National Natural Science Foundation of China(32070839)

National Natural Science Foundation of China(32100913)

National Natural Science Foundation of China(82260291)

National Natural Science Foundation of China(32100686)

China Postdoctoral Science Foundation(2021M700972)

Institution of Higher Education Projects of Building Firstclass Discipline Construction in Ningxia Region(Biology)(NXYLXK2017B05)

Doctoral Startup Foundation of Guizhou Medical University([2020]038)

出版年

2024

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

参考文献量58

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