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Open accessJournal ArticleDOI: 10.1016/J.CMET.2021.01.004

Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process

02 Mar 2021-Cell Metabolism (Elsevier BV)-Vol. 33, Iss: 3
Abstract: Polycystic ovary syndrome (PCOS) is the most common reproductive and metabolic disorder affecting women of reproductive age PCOS has a strong heritable component, but its pathogenesis has been unclear Here, we performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control and third-generation PCOS-like mice We found that DNA hypomethylation regulates key genes associated with PCOS and that several of the differentially methylated genes are also altered in blood samples from women with PCOS compared with healthy controls Based on this insight, we treated the PCOS mouse model with the methyl group donor S-adenosylmethionine and found that it corrected their transcriptomic, neuroendocrine, and metabolic defects These findings show that the transmission of PCOS traits to future generations occurs via an altered landscape of DNA methylation and propose methylome markers as a possible diagnostic landmark for the condition, while also identifying potential candidates for epigenetic-based therapy

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Topics: Polycystic ovary (61%), DNA methylation (54%), Epigenetics (54%) ... read more
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13 results found


Journal ArticleDOI: 10.1210/ENDREV/BNAB012
14 Apr 2021-Endocrine Reviews
Abstract: Anti-Mullerian hormone (AMH), also called Mullerian inhibiting substance, was shown to be synthesized by the ovary in the eighties. This article reviews the main findings of the past 20 years on the regulation of the expression of AMH and its specific receptor AMHR2 by granulosa cells, the mechanism of action of AMH, the different roles it plays in the reproductive organs, its clinical utility and its involvement in the principal pathological conditions affecting women. The findings in respect of regulation tell us that AMH and AMHR2 expression is mainly regulated by Bone Morphogenetic Proteins, gonadotropins and estrogens. It has now been established that AMH regulates the different steps of folliculogenesis and that it has neuroendocrine effects. On the other hand, the importance of serum AMH as a reliable marker of ovarian reserve and as a useful tool in the prediction of the polycystic ovary syndrome (PCOS) and primary ovarian failure has also been acknowledged. Last but not least, a large body of evidence points to the involvement of AMH in the pathogenesis of PCOS.

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Topics: Anti-Müllerian hormone (62%), Polycystic ovary (57%), Anti-Müllerian hormone receptor (53%) ... read more

1 Citations


Open accessJournal ArticleDOI: 10.3389/FCELL.2021.682060
Weijie Yang1, Yerong Ma1, Jiamin Jin1, Peipei Ren1  +8 moreInstitutions (1)
Abstract: Cyclophosphamide (CTX) is widely used in various cancer therapies and in immunosuppression, and patients can still have babies after CTX chemotherapy. CTX directly causes primordial follicle loss with overactivation and DNA damage-induced apoptosis. Previous studies have shown that maternal exposure to CTX before conception increases the incidence of birth abnormalities and alters the methylation of genes in the oocytes of offspring. Mice were treated with a single dose of CTX (100 mg/kg) at post-natal day 21 and sacrificed 47 days later when primordial follicles surviving chemotherapy developed to the antral stage. Acute DNA damage and acceleration of the activation of primordial follicles after CTX treatment were repaired within several days, but the remaining follicle numbers remarkably decrease. Although partial surviving primordial follicle were developed to mature oocyte, oocyte quality hemostasis was impaired exhibiting aberrant meiosis progression, abnormal spindle and aneuploidy, mitochondrial dysfunction and increased endoplasmic reticulum stress. Thereafter, embryo development competency significantly decreased with fewer blastocyst formation after CTX exposure. CTX treatment resulted in alteration of DNA methylations and histone modifications in fully grown GV oocytes. Single-cell RNA-seq revealed CTX treatment suppressed multiple maternal genes' transcription including many methyltransferases and maternal factor YAP1, which probably accounts for low quality of CTX-repaired oocyte. In vitro addition of lysophosphatidic acid (LPA) to embryo culture media to promote YAP1 nuclear localization improved CTX-repaired embryo developmental competence. This study provides evidence for the consistent toxic effect of CTX exposure during follicle development, and provide a new mechanism and new insights into future clinical interventions for fertility preservation.

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Topics: Folliculogenesis (57%), Oocyte (51%), Embryo culture (51%)

1 Citations


Journal ArticleDOI: 10.1016/J.CMET.2021.02.008
David H. Abbott1, Daniel A. Dumesic2Institutions (2)
02 Mar 2021-Cell Metabolism
Abstract: Polycystic ovary syndrome (PCOS) is a prevalent reproductive-metabolic disorder with poorly understood etiology. Mimouni et al. (2021) demonstrate global genomic DNA hypomethylation in women with PCOS and their daughters, and in F3 generation PCOS-like mice, together with substantial normalization of PCOS-like mice by methyl donor dietary supplementation.

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Topics: Polycystic ovary (62%)

1 Citations


Open accessBook ChapterDOI: 10.1016/B978-0-12-823045-9.00009-2
01 Jan 2022-
Abstract: Up to 20% of women in their reproductive years have polycystic ovary syndrome (PCOS), a complex reproductive, metabolic, and behavioral women's disorder bestowing subfertility, increased obesity, and type 2 diabetes, as well as increased risk of anxiety and depression. While its origins are unknown, PCOS is highly heritable and increasing evidence suggests a combination of genetic, epigenetic, and developmental origins commencing during hyperandrogenic gestations. A reliable biomarker of female fetal hyperandrogenism, elongated anogenital distance, found in newborn daughters of women with PCOS, and in adult PCOS women, considered together with repeated confirmation of PCOS-like phenotype induction in nonhuman primate, sheep, rat, and mouse models by experimental induction of fetal female hyperandrogenism, and transgenerational transmission of induced PCOS-like phenotypes, all suggest in utero hyperandrogenic origins for PCOS pathogenesis. This brief review will focus on the evidence for PCOS pathogenesis in women and underlying molecular gateways enabling its development during hyperandrogenic gestations in animal models.

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Topics: Polycystic ovary (59%), Hyperandrogenism (52%)

Open accessJournal ArticleDOI: 10.1038/S41598-021-99867-9
Heyun Ruan1, Fang Yang1, Lingjie Deng1, Dongmei Yang1  +3 moreInstitutions (1)
14 Oct 2021-Scientific Reports
Abstract: The thalassemia of Hemoglobin H-Constant Spring disease (HbH-CS) is the most common type of Thalassemia in non-transfusion thalassemia. Interestingly, the clinical manifestations of the same genotype of thalassemia can be vastly different, likely due to epigenetic regulation. Here, we used microarray technology to reveal the epigenetic regulation of m6A in modifiable diseases and demonstrated a role of BCL2A1 in disease regulation. In this study, we revealed that methylating enzyme writers including METTL16, WTAP, CBLL1, RBM15B, and ZC3H13 displayed low expression and the demethylating enzyme ALKBH5, along with reader proteins including IGF2BP2 and YTHDF3 exhibited high expression. In addition, BCL2A1 was hypo-methylated and showed low expression. We also revealed that the BCL2A1 methylation level and IGF2BP2 expression were negatively correlated. Additionally, the mRNAs expression between ALKBH5 and IGF2BP2 were positively correlated. In HbH-CS, most genes were hypo-methylated. This included BCL2A1, which may play an important role in the process of red blood cell differentiation and development of HbH-CS. Moreover, the mRNA-M6A methylation status may be regulated by the demethylating enzyme ALKBH5 via IGF2BP2.

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Topics: RNA methylation (55%), Thalassemia (55%), Epigenetics (54%) ... read more

References
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83 results found


Journal ArticleDOI: 10.1006/METH.2001.1262
01 Dec 2001-Methods
Abstract: The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data.

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Topics: MicroRNA 34a (52%), Cell wall organization (50%)

116,500 Citations


Journal ArticleDOI: 10.1111/J.2517-6161.1995.TB02031.X
Abstract: SUMMARY The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses -the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferronitype procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.

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Topics: False discovery rate (72%), Per-comparison error rate (66%), False coverage rate (63%) ... read more

71,936 Citations


Open accessJournal ArticleDOI: 10.1186/S13059-014-0550-8
05 Dec 2014-Genome Biology
Abstract: In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html .

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Topics: MRNA Sequencing (54%), Integrator complex (51%), Count data (50%) ... read more

29,675 Citations


Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTS635
01 Jan 2013-Bioinformatics
Abstract: Motivation Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. Results To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. Availability and implementation STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.

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Topics: MRNA Sequencing (57%)

20,172 Citations


Open accessJournal ArticleDOI: 10.1186/GB-2009-10-3-R25
04 Mar 2009-Genome Biology
Abstract: Bowtie is an ultrafast, memory-efficient alignment program for aligning short DNA sequence reads to large genomes. For the human genome, Burrows-Wheeler indexing allows Bowtie to align more than 25 million reads per CPU hour with a memory footprint of approximately 1.3 gigabytes. Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches. Multiple processor cores can be used simultaneously to achieve even greater alignment speeds. Bowtie is open source http://bowtie.cbcb.umd.edu.

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Topics: Hybrid genome assembly (51%)

18,079 Citations