Skip to main content
Top
Published in: Archives of Gynecology and Obstetrics 5/2021

01-05-2021 | Epigenetics | Gynecologic Endocrinology and Reproductive Medicine

Decreased expression of m6A demethylase FTO in ovarian aging

Authors: Xiaoyan Sun, Yigan Zhang, Yuping Hu, Junxia An, Lifei Li, Yiqing Wang, Xuehong Zhang

Published in: Archives of Gynecology and Obstetrics | Issue 5/2021

Login to get access

Abstract

Purpose

N6-methyladenosine (m6A) and demethylase fat mass and obesity-associated protein (FTO) were reported to be associated with oocyte development and maturation. But the relationship between FTO and ovarian aging was still unclear. This study was aimed at investigating the FTO expression level and the m6A content during ovarian aging.

Methods

The expression level of FTO and the content of m6A RNA methylation in human follicular fluid (FF), granulosa cells (GCs) and mouse ovary from different age groups were studied by ELISA, WB, qRT-PCR, IHC and m6A Colorimetric.

Results

Human FF ELISA quantified that the level of FTO protein decreased with age (P = 0.025). QRT-PCR results showed that the relative expression of FTO in human GCs was lower in the elderly group than in the young group (P = 0.012). FTO mRNA and protein expression levels were lower in the ovary of 32-week-old mice than in 3- and 8-week-old mice (P < 0.05). Immunohistochemistry showed FTO was relatively decreased in 32-week-old mice (P < 0.05). The m6A content in total RNA from old human GCs and ovary from 32-week-old mice was significantly higher compared with the younger ones.

Conclusions

In human FF, GCs and mouse ovary, the expression of FTO decreased while the content of m6A increased with aging. However, the inner mechanism still needs further investigation.
Literature
1.
go back to reference Zhang J, Chen Q, Du D et al (2019) Can ovarian aging be delayed by pharmacological strategies? Aging (Albany NY) 11:817–832CrossRef Zhang J, Chen Q, Du D et al (2019) Can ovarian aging be delayed by pharmacological strategies? Aging (Albany NY) 11:817–832CrossRef
2.
go back to reference Liu KE (2017) Case A. No. 346-advanced reproductive age and fertility. J Obstet Gynaecol Can 39:685–695CrossRef Liu KE (2017) Case A. No. 346-advanced reproductive age and fertility. J Obstet Gynaecol Can 39:685–695CrossRef
3.
go back to reference Li L, Wang Z (2018) Ovarian aging and osteoporosis. Adv Exp Med Biol 1086:199–215CrossRef Li L, Wang Z (2018) Ovarian aging and osteoporosis. Adv Exp Med Biol 1086:199–215CrossRef
4.
go back to reference Quinn MM, Cedars MI (2018) Cardiovascular health and ovarian aging. Fertil Steril 110:790–793CrossRef Quinn MM, Cedars MI (2018) Cardiovascular health and ovarian aging. Fertil Steril 110:790–793CrossRef
5.
go back to reference Laisk T, Tšuiko O, Jatsenko T et al (2019) Demographic and evolutionary trends in ovarian function and aging. Hum Reprod Update 25:34–50PubMed Laisk T, Tšuiko O, Jatsenko T et al (2019) Demographic and evolutionary trends in ovarian function and aging. Hum Reprod Update 25:34–50PubMed
7.
go back to reference Briley SM, Jasti S, McCracken JM et al (2016) Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction 152:245–260CrossRef Briley SM, Jasti S, McCracken JM et al (2016) Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction 152:245–260CrossRef
8.
go back to reference Xu X, Chen X, Zhang X et al (2017) Impaired telomere length and telomerase activity in peripheral blood leukocytes and granulosa cells in patients with biochemical primary ovarian insufficiency. Hum Reprod 32:201–207PubMed Xu X, Chen X, Zhang X et al (2017) Impaired telomere length and telomerase activity in peripheral blood leukocytes and granulosa cells in patients with biochemical primary ovarian insufficiency. Hum Reprod 32:201–207PubMed
9.
go back to reference Frye M, Harada BT, Behm M et al (2018) RNA modifications modulate gene expression during development. Science 361:1346–1349CrossRef Frye M, Harada BT, Behm M et al (2018) RNA modifications modulate gene expression during development. Science 361:1346–1349CrossRef
10.
go back to reference He L, Li H, Wu A et al (2019) Functions of N6-methyladenosine and its role in cancer. Mol Cancer 18:176CrossRef He L, Li H, Wu A et al (2019) Functions of N6-methyladenosine and its role in cancer. Mol Cancer 18:176CrossRef
11.
go back to reference Batista PJ, The RNA (2017) Modification N(6)-methyladenosine and its implications in human disease. Genom Proteomics Bioinform 15:154–163CrossRef Batista PJ, The RNA (2017) Modification N(6)-methyladenosine and its implications in human disease. Genom Proteomics Bioinform 15:154–163CrossRef
12.
go back to reference Hu Y, Ouyang Z, Sui X et al (2020) Oocyte competence is maintained by m(6)A methyltransferase KIAA1429-mediated RNA metabolism during mouse follicular development. Cell Death Differ 27:2468–2483CrossRef Hu Y, Ouyang Z, Sui X et al (2020) Oocyte competence is maintained by m(6)A methyltransferase KIAA1429-mediated RNA metabolism during mouse follicular development. Cell Death Differ 27:2468–2483CrossRef
13.
go back to reference Sui X, Hu Y, Ren C et al (2020) METTL3-mediated m(6)A is required for murine oocyte maturation and maternal-to-zygotic transition. Cell Cycle 19:391–404CrossRef Sui X, Hu Y, Ren C et al (2020) METTL3-mediated m(6)A is required for murine oocyte maturation and maternal-to-zygotic transition. Cell Cycle 19:391–404CrossRef
14.
go back to reference Ivanova I, Much C, Di Giacomo M et al (2017) The RNA m(6)A reader YTHDF2 is essential for the post-transcriptional regulation of the maternal transcriptome and oocyte competence. Mol Cell 67(1059–1067):e4 Ivanova I, Much C, Di Giacomo M et al (2017) The RNA m(6)A reader YTHDF2 is essential for the post-transcriptional regulation of the maternal transcriptome and oocyte competence. Mol Cell 67(1059–1067):e4
15.
go back to reference Jia G, Fu Y, Zhao X et al (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7:885–887CrossRef Jia G, Fu Y, Zhao X et al (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7:885–887CrossRef
16.
go back to reference Zhao X, Yang Y, Sun BF et al (2014) FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res 24:1403–1419CrossRef Zhao X, Yang Y, Sun BF et al (2014) FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res 24:1403–1419CrossRef
17.
go back to reference Boissel S, Reish O, Proulx K et al (2009) Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet 85:106–111CrossRef Boissel S, Reish O, Proulx K et al (2009) Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet 85:106–111CrossRef
18.
go back to reference Ding C, Zou Q, Ding J et al (2018) Increased N6-methyladenosine causes infertility is associated with FTO expression. J Cell Physiol 233:7055–7066CrossRef Ding C, Zou Q, Ding J et al (2018) Increased N6-methyladenosine causes infertility is associated with FTO expression. J Cell Physiol 233:7055–7066CrossRef
19.
go back to reference Wang YK, Yu XX, Liu YH et al (2018) Reduced nucleic acid methylation impairs meiotic maturation and developmental potency of pig oocytes. Theriogenology 121:160–167CrossRef Wang YK, Yu XX, Liu YH et al (2018) Reduced nucleic acid methylation impairs meiotic maturation and developmental potency of pig oocytes. Theriogenology 121:160–167CrossRef
20.
go back to reference Kasowitz SD, Ma J, Anderson SJ et al (2018) Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. PLoS Genet 14:e1007412CrossRef Kasowitz SD, Ma J, Anderson SJ et al (2018) Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. PLoS Genet 14:e1007412CrossRef
21.
go back to reference Xia H, Zhong C, Wu X et al (2018) Mettl3 mutation disrupts gamete maturation and reduces fertility in Zebrafish. Genetics 208:729–743CrossRef Xia H, Zhong C, Wu X et al (2018) Mettl3 mutation disrupts gamete maturation and reduces fertility in Zebrafish. Genetics 208:729–743CrossRef
22.
go back to reference Huang B, Ding C, Zou Q et al (2019) Cyclophosphamide regulates N6-methyladenosine and m6A RNA enzyme levels in human granulosa cells and in ovaries of a premature ovarian aging mouse model. Front Endocrinol (Lausanne) 10:415CrossRef Huang B, Ding C, Zou Q et al (2019) Cyclophosphamide regulates N6-methyladenosine and m6A RNA enzyme levels in human granulosa cells and in ovaries of a premature ovarian aging mouse model. Front Endocrinol (Lausanne) 10:415CrossRef
23.
go back to reference Li F, Zhang C, Zhang G (2019) m6A RNA methylation controls proliferation of human glioma cells by influencing cell apoptosis. Cytogenet Genome Res 159:119–125CrossRef Li F, Zhang C, Zhang G (2019) m6A RNA methylation controls proliferation of human glioma cells by influencing cell apoptosis. Cytogenet Genome Res 159:119–125CrossRef
24.
go back to reference Min KW, Zealy RW, Davila S et al (2018) Profiling of m6A RNA modifications identified an age-associated regulation of AGO2 mRNA stability. Aging Cell 17:e12753CrossRef Min KW, Zealy RW, Davila S et al (2018) Profiling of m6A RNA modifications identified an age-associated regulation of AGO2 mRNA stability. Aging Cell 17:e12753CrossRef
25.
go back to reference Mathiyalagan P, Adamiak M, Mayourian J et al (2019) FTO-dependent N(6)-methyladenosine regulates cardiac function during remodeling and repair. Circulation 139:518–532CrossRef Mathiyalagan P, Adamiak M, Mayourian J et al (2019) FTO-dependent N(6)-methyladenosine regulates cardiac function during remodeling and repair. Circulation 139:518–532CrossRef
26.
go back to reference Niu Y, Lin Z, Wan A et al (2019) RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer 18:46CrossRef Niu Y, Lin Z, Wan A et al (2019) RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer 18:46CrossRef
27.
go back to reference Zou D, Dong L, Li C et al (2019) The m(6)A eraser FTO facilitates proliferation and migration of human cervical cancer cells. Cancer Cell Int 19:321CrossRef Zou D, Dong L, Li C et al (2019) The m(6)A eraser FTO facilitates proliferation and migration of human cervical cancer cells. Cancer Cell Int 19:321CrossRef
28.
go back to reference Yang Y, Shen F, Huang W et al (2019) Glucose is involved in the dynamic regulation of m6A in patients with type 2 diabetes. J Clin Endocrinol Metab 104:665–673CrossRef Yang Y, Shen F, Huang W et al (2019) Glucose is involved in the dynamic regulation of m6A in patients with type 2 diabetes. J Clin Endocrinol Metab 104:665–673CrossRef
29.
go back to reference Church C, Moir L, McMurray F et al (2010) Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet 42:1086–1092CrossRef Church C, Moir L, McMurray F et al (2010) Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet 42:1086–1092CrossRef
Metadata
Title
Decreased expression of m6A demethylase FTO in ovarian aging
Authors
Xiaoyan Sun
Yigan Zhang
Yuping Hu
Junxia An
Lifei Li
Yiqing Wang
Xuehong Zhang
Publication date
01-05-2021
Publisher
Springer Berlin Heidelberg
Keyword
Epigenetics
Published in
Archives of Gynecology and Obstetrics / Issue 5/2021
Print ISSN: 0932-0067
Electronic ISSN: 1432-0711
DOI
https://doi.org/10.1007/s00404-020-05895-7

Other articles of this Issue 5/2021

Archives of Gynecology and Obstetrics 5/2021 Go to the issue