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      Dynamic Changes of DNA Methylation and Transcriptome Expression in Porcine Ovaries during Aging

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          Abstract

          The biological function of human ovaries declines along with aging. To identify the underlying molecular changes during ovarian aging, pigs were used as model animals. Genome-wide DNA methylation and transcriptome-wide RNA expression analyses were performed via high-throughput sequencing of ovaries from young pigs (180 days, puberty stage of first ovulation) and old pigs (eight years, reproductive exhaustion stage). The results identified 422 different methylation regions between old and young pigs; furthermore, a total of 2,243 mRNAs, 95 microRNAs, 248 long noncoding RNAs (lncRNAs), and 116 circular RNAs (circRNAs) were differentially expressed during both developmental stages. Gene ontology analysis showed that these genes related to different methylation and expression are involved in the ovarian aging cycle. Specifically, these are involved in cell apoptosis, death effector domain binding, embryonic development, reproduction and fertilization process, ovarian cumulus expansion, and the ovulation cycle. Multigroup cooperative control relationships were also assessed, and competing endogenous RNA (ceRNA) networks were constructed in the ovarian aging cycle. These data will help to clarify ovary age-associated potential molecular changes in DNA methylation and transcriptional patterns over time.

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          Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche

          Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality 1 . Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation 2,3 , but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
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            Epigenetic events in mammalian germ-cell development: reprogramming and beyond.

            The epigenetic profile of germ cells, which is defined by modifications of DNA and chromatin, changes dynamically during their development. Many of the changes are associated with the acquisition of the capacity to support post-fertilization development. Our knowledge of this aspect has greatly increased- for example, insights into how the re-establishment of parental imprints is regulated. In addition, an emerging theme from recent studies is that epigenetic modifiers have key roles in germ-cell development itself--for example, epigenetics contributes to the gene-expression programme that is required for germ-cell development, regulation of meiosis and genomic integrity. Understanding epigenetic regulation in germ cells has implications for reproductive engineering technologies and human health.
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              Spatio-temporal regulation of circular RNA expression during porcine embryonic brain development

              Background Recently, thousands of circular RNAs (circRNAs) have been discovered in various tissues and cell types from human, mouse, fruit fly and nematodes. However, expression of circRNAs across mammalian brain development has never been examined. Results Here we profile the expression of circRNA in five brain tissues at up to six time-points during fetal porcine development, constituting the first report of circRNA in the brain development of a large animal. An unbiased analysis reveals a highly complex regulation pattern of thousands of circular RNAs, with a distinct spatio-temporal expression profile. The amount and complexity of circRNA expression was most pronounced in cortex at day 60 of gestation. At this time-point we find 4634 unique circRNAs expressed from 2195 genes out of a total of 13,854 expressed genes. Approximately 20 % of the porcine splice sites involved in circRNA production are functionally conserved between mouse and human. Furthermore, we observe that “hot-spot” genes produce multiple circRNA isoforms, which are often differentially expressed across porcine brain development. A global comparison of porcine circRNAs reveals that introns flanking circularized exons are longer than average and more frequently contain proximal complementary SINEs, which potentially can facilitate base pairing between the flanking introns. Finally, we report the first use of RNase R treatment in combination with in situ hybridization to show dynamic subcellular localization of circRNA during development. Conclusions These data demonstrate that circRNAs are highly abundant and dynamically expressed in a spatio-temporal manner in porcine fetal brain, suggesting important functions during mammalian brain development. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0801-3) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi
                2314-6133
                2314-6141
                2019
                30 October 2019
                : 2019
                : 8732023
                Affiliations
                1Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, Sichuan 625014, China
                2Sichuan Weimu Modern Agricultural Science and Technology Co., Ltd., Chengdu, Sichuan 611536, China
                3Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
                Author notes

                Academic Editor: Thomas Lufkin

                Author information
                https://orcid.org/0000-0001-7342-0880
                https://orcid.org/0000-0001-8681-7684
                https://orcid.org/0000-0003-0485-3599
                https://orcid.org/0000-0002-9568-557X
                Article
                10.1155/2019/8732023
                6874880
                31781648
                75d20e5d-c2c0-4f01-85f1-fd465a0580a2
                Copyright © 2019 Xiaoyu Xi et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 February 2019
                : 25 June 2019
                : 30 September 2019
                Funding
                Funded by: National Key R&D Program of China
                Award ID: 2018YFD0501204
                Funded by: Chengdu Local Good Varieties of Livestock and Poultry Resources Protection and Exploitation and Utilization of Construction Projects
                Funded by: Sichuan Agricultural Science and Technology Transformation Fund Project–Breeding and Demonstration of Grain-Saving and Resistance Lean Pig Line
                Award ID: 2018NZZJ017
                Categories
                Research Article

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