Attenuated expression of MTR in both prenatally androgenized mice and women with the hyperandrogenic phenotype of PCOS

Lei, Lei; Ding, Lijun; Su, Jing; Liu, Mengyuan; Shi, Qingqing; Zhou, Jianjun; Sun, Haixiang; Yan, Guijun

doi:10.1371/journal.pone.0187427

Cited by 16 publications

(11 citation statements)

References 45 publications

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“…It transpires that the majority of genes encoding 1C enzymes are steroid-responsive, accounting for differences in expression/activity during both the estrous and menstrual cycles of mammals, as well as during pregnancy [128]. Significantly, the reported observations of prenatal androgenization in mice are consistent with reduced granulosa cell MTR expression and serum SAM concentrations in hyperandrogenic PCOS women [135].…”

Section: Prenatal Diet Epigenetics and Pcosmentioning

confidence: 90%

“…Similarly, prenatal androgen exposure in sheep led to upregulation of H3K9me3 (gene repressive), and H3K27ac and H3K9ac (both gene activating) marks in the ovaries of adult offspring, affecting genes involved in steroid biosynthesis and inflammation [134]. In a separate study undertaken in mice, blood concentrations of the methyl donor SAM were reduced in prenatally androgenized offspring in line with attenuated ovarian expression of both Mtr and Bhmt (two 1C cycle enzymes involved in the remethylation of Hcy to methionine (Figure 3)) [135]. It transpires that the majority of genes encoding 1C enzymes are steroid-responsive, accounting for differences in expression/activity during both the estrous and menstrual cycles of mammals, as well as during pregnancy [128].…”

Section: Prenatal Diet Epigenetics and Pcosmentioning

confidence: 94%

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Polycystic Ovary Syndrome: A Brain Disorder Characterized by Eating Problems Originating during Puberty and Adolescence

Steegers‐Theunissen

Wiegel

Jansen

et al. 2020

IJMS

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Polycystic ovary syndrome (PCOS) is an endocrine condition associated with reproductive and psychiatric disorders, and with obesity. Eating disorders, such as bulimia and recurrent dieting, are also linked to PCOS. They can lead to the epigenetic dysregulation of the hypothalamic–pituitary–gonadal (HPG) axis, thereby impacting on ovarian folliculogenesis. We postulate that PCOS is induced by psychological distress and episodes of overeating and/or dieting during puberty and adolescence, when body dissatisfaction and emotional distress are often present. We propose that upregulated activation of the central HPG axis during this period can be epigenetically altered by psychological stressors and by bulimia/recurrent dieting, which are common during adolescence and which can lead to PCOS. This hypothesis is based on events that occur during a largely neglected stage of female reproductive development. To date, most research into the origins of PCOS has focused on the prenatal induction of this disorder, particularly in utero androgenization and the role of anti-Müllerian hormone. Establishing causality in our peripubertal model requires prospective cohort studies from infancy. Mechanistic studies should consider the role of the gut microbiota in addition to the epigenetic regulation of (neuro) hormones. Finally, clinicians should consider the importance of underlying chronic psychological distress and eating disorders in PCOS.

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Section: Prenatal Diet Epigenetics and Pcosmentioning

confidence: 90%

Section: Prenatal Diet Epigenetics and Pcosmentioning

confidence: 94%

Polycystic Ovary Syndrome: A Brain Disorder Characterized by Eating Problems Originating during Puberty and Adolescence

Steegers‐Theunissen

Wiegel

Jansen

et al. 2020

IJMS

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“…The mice were euthanized using the anesthetic chloral hydrate, and ovarian tissues were subsequently harvested. The DHT-induced PNA mouse model from that laboratory was used in some research, and the data on metabolic, hormonal, and reproductive/ovarian parameters for the PNA mouse model have been previously published ( Lei et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

Integrated Transcriptomic and Epigenetic Study of PCOS: Impact of Map3k1 and Map1lc3a Promoter Methylation on Autophagy

Qin

Zhao

et al. 2021

Front. Genet.

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Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous endocrine and metabolic disorder in women of reproductive age. Epigenetic mechanisms contribute to the development of PCOS. Nevertheless, the role of DNA methylation in the development of PCOS remains unclear. To investigate the molecular mechanisms underlying the hyperandrogenic phenotype of PCOS, dihydrotestosterone (DHT)-induced prenatally androgenized (PNA) mice were used to mimic this phenotype. Ovarian samples from PNA and control mice were subjected to methyl-CpG-binding domain (MBD)-seq and RNA-seq, and validation was conducted using methylation-specific polymerase chain reaction (MSP) and quantitative real-time PCR (RT-qPCR). Immunohistochemical analysis (using anti-LC3II antibody) and transmission electron microscopy were conducted using ovarian tissue sections (which included granulosa cells) from PNA and control mice. There were 857 genes with differentially methylated promoter regions and 3,317 differentially expressed genes (DEGs) in the PNA mice compared to the control mice. Downregulation of Dnmt1 (which encodes DNA methyltransferase 1), accompanied by global hypomethylation, was observed in the PNA mice compared to the control mice. The promoter regions of Map3k1 (which encodes MEKK1) and Map1lc3a (which encodes LC3II) were hypomethylated, accompanied by upregulation of Map3k1 and Map1lc3a mRNA expression. The autophagy profiling results showed that LC3II protein expression and autophagosomes were significantly increased in the granulosa cells of PNA mice. Additionally, the mRNA expression of genes related to the mitogen-activated protein kinase (MAPK)/p53 pathway (Mapk14, Mapkapk3, and Trp53) and the autophagy-related gene Becn1 were significantly increased. DHT could change the DNA methylation and transcription level of Map3k1 and lead to an activation of autophagy in granulosa cells. These observations indicated that the change in autophagy may be driven by MAPK/p53 pathway activation, which may have been caused by DHT-induced transcriptional, and the methylation level changed of the key upstream gene Map3k1. Our study provides a novel genetic basis and new insights regarding the pathogenesis of PCOS.

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“…Co-expression analysis is widely used to elucidate the relationship between lncRNAs and messenger RNAs (mRNAs) (13). It can also be used to discover key lncRNAs and to understand their underlying mechanisms in important diseases including PCOS.…”

Section: Introductionmentioning

confidence: 99%

Analysis of LncRNA-mRNA Co-Expression Profiles in Patients With Polycystic Ovary Syndrome: A Pilot Study

Sun

Gao

et al. 2021

Front. Immunol.

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PurposeThis study aimed to investigate the profiles of messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) in peripheral blood samples collected from polycystic ovary syndrome (PCOS) patients. In addition, an in-depth bioinformatics analysis regarding the lncRNA-mRNA co-expression network was performed.MethodsHigh-throughput sequencing was used to measure the profiles of mRNAs and lncRNAs expressed in the peripheral blood samples isolated from six patients (three patients with PCOS and three normal women). In addition, five differentially expressed lncRNAs were chosen to validate the results of high-throughput sequencing by quantitative RT-PCR (qRT-PCR). Furthermore, a lncRNA-mRNA co-expression network was constructed using the Cytoscape software.ResultsA total of 14,276 differentially expressed mRNAs and 4,048 differentially expressed lncRNAs were obtained from the RNA-seq analysis of PCOS patients and healthy controls (adjusted q-value < 0.05, Fold change >2.0).The qRT-PCR results were consistent with the data obtained through high-throughput sequencing. Gene ontology (GO) and KEGG pathway analyses showed that the differentially expressed mRNAs were enriched in the chemokine signaling pathway. In addition, the analysis of the lncRNA-mRNA co-expression network of the chemokine signaling pathway showed the involvement of 6 mRNAs and 42 lncRNAs.ConclusionClusters of mRNAs and lncRNAs were aberrantly expressed in the peripheral blood of PCOS patients compared with the controls. In addition, several pairs of lncRNA-mRNAs in the chemokine signaling pathway may be related to PCOS genetically.

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Attenuated expression of MTR in both prenatally androgenized mice and women with the hyperandrogenic phenotype of PCOS

Cited by 16 publications

References 45 publications

Polycystic Ovary Syndrome: A Brain Disorder Characterized by Eating Problems Originating during Puberty and Adolescence

Polycystic Ovary Syndrome: A Brain Disorder Characterized by Eating Problems Originating during Puberty and Adolescence

Integrated Transcriptomic and Epigenetic Study of PCOS: Impact of Map3k1 and Map1lc3a Promoter Methylation on Autophagy

Analysis of LncRNA-mRNA Co-Expression Profiles in Patients With Polycystic Ovary Syndrome: A Pilot Study

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