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      Reprogramming of ovarian aging epigenome by resveratrol

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          Abstract

          Resveratrol is an antiaging, antioxidant, and anti-inflammatory natural polyphenolic compound. Growing evidence indicates that resveratrol has potential therapeutic effects for improving aging ovarian function. However, the mechanisms underlying prolonged reproductive longevity remain elusive. We found that resveratrol ameliorates ovarian aging transcriptome, some of which are associated with specific changes in methylome. In addition to known aging transcriptome of oocytes and granulosa cells such as decline in oxidoreductase activity, metabolism and mitochondria function, and elevated DNA damage and apoptosis, actin cytoskeleton are notably downregulated with age, and these defects are mostly rescued by resveratrol. Moreover, the aging-associated hypermethylation of actin cytoskeleton is decreased by resveratrol. In contrast, deletion of Tet2, involved in DNA demethylation, abrogates resveratrol-reprogrammed ovarian aging transcriptome. Consistently, Tet2 deficiency results in additional altered pathways as shown by increased mTOR and Wnt signaling, as well as reduced DNA repair and actin cytoskeleton with mouse age. Moreover, genes associated with oxidoreductase activity and oxidation–reduction process were hypermethylated in Tet2-deficient oocytes from middle-age mice treated with resveratrol, indicating that loss of Tet2 abolishes the antioxidant effect of resveratrol. Taking together, our finding provides a comprehensive landscape of transcriptome and epigenetic changes associated with ovarian aging that can be reprogrammed by resveratrol administration, and suggests that aberrantly increased DNA methylation by Tet2 deficiency promotes additional aging epigenome that cannot be effectively restored to younger state by resveratrol.

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          HISAT: a fast spliced aligner with low memory requirements.

          HISAT (hierarchical indexing for spliced alignment of transcripts) is a highly efficient system for aligning reads from RNA sequencing experiments. HISAT uses an indexing scheme based on the Burrows-Wheeler transform and the Ferragina-Manzini (FM) index, employing two types of indexes for alignment: a whole-genome FM index to anchor each alignment and numerous local FM indexes for very rapid extensions of these alignments. HISAT's hierarchical index for the human genome contains 48,000 local FM indexes, each representing a genomic region of ∼64,000 bp. Tests on real and simulated data sets showed that HISAT is the fastest system currently available, with equal or better accuracy than any other method. Despite its large number of indexes, HISAT requires only 4.3 gigabytes of memory. HISAT supports genomes of any size, including those larger than 4 billion bases.
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            The Hallmarks of Aging

            Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.
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              TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions

              TopHat is a popular spliced aligner for RNA-sequence (RNA-seq) experiments. In this paper, we describe TopHat2, which incorporates many significant enhancements to TopHat. TopHat2 can align reads of various lengths produced by the latest sequencing technologies, while allowing for variable-length indels with respect to the reference genome. In addition to de novo spliced alignment, TopHat2 can align reads across fusion breaks, which can occur after genomic translocations. TopHat2 combines the ability to identify novel splice sites with direct mapping to known transcripts, producing sensitive and accurate alignments, even for highly repetitive genomes or in the presence of pseudogenes. TopHat2 is available at http://ccb.jhu.edu/software/tophat.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PNAS Nexus
                PNAS Nexus
                pnasnexus
                PNAS Nexus
                Oxford University Press
                2752-6542
                February 2023
                24 December 2022
                24 December 2022
                : 2
                : 2
                : pgac310
                Affiliations
                Department of Genetics and Cell Biology, College of Life Science, Nankai University , Tianjin 300071, China
                State Key Laboratory of Medicinal Chemical Biology, Nankai University , Tianjin, 300350, China
                Department of Genetics and Cell Biology, College of Life Science, Nankai University , Tianjin 300071, China
                State Key Laboratory of Medicinal Chemical Biology, Nankai University , Tianjin, 300350, China
                CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences , 100101 Beijing, China
                Department of Genetics and Cell Biology, College of Life Science, Nankai University , Tianjin 300071, China
                State Key Laboratory of Medicinal Chemical Biology, Nankai University , Tianjin, 300350, China
                Department of Genetics and Cell Biology, College of Life Science, Nankai University , Tianjin 300071, China
                State Key Laboratory of Medicinal Chemical Biology, Nankai University , Tianjin, 300350, China
                Department of Genetics and Cell Biology, College of Life Science, Nankai University , Tianjin 300071, China
                State Key Laboratory of Medicinal Chemical Biology, Nankai University , Tianjin, 300350, China
                Department of Genetics and Cell Biology, College of Life Science, Nankai University , Tianjin 300071, China
                State Key Laboratory of Medicinal Chemical Biology, Nankai University , Tianjin, 300350, China
                Department of Zoology, College of Life Science, Nankai University , Tianjin 300071, China
                Department of Biochemistry and Molecular Biology, College of Life Science, Nankai University , Tianjin 300071, China
                Department of Genetics and Cell Biology, College of Life Science, Nankai University , Tianjin 300071, China
                State Key Laboratory of Medicinal Chemical Biology, Nankai University , Tianjin, 300350, China
                CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences , 100101 Beijing, China
                Department of Genetics and Cell Biology, College of Life Science, Nankai University , Tianjin 300071, China
                State Key Laboratory of Medicinal Chemical Biology, Nankai University , Tianjin, 300350, China
                Institute of Translational Medicine, Nankai Union Medical Center, Nankai University , Tianjin 300000, China
                Author notes
                To whom correspondence should be addressed. zhuzhengmao@ 123456nankai.edu.cn
                To whom correspondence should be addressed. liuj@ 123456big.ac.cn
                To whom correspondence should be addressed. liulin@ 123456nankai.edu.cn

                These authors contributed equally: Mo Gou, Jie Li, and Lizhi Yi

                Author information
                https://orcid.org/0000-0003-1492-8988
                https://orcid.org/0000-0002-8734-8020
                https://orcid.org/0000-0001-9881-6830
                Article
                pgac310
                10.1093/pnasnexus/pgac310
                9896145
                36743471
                428f909f-754f-449b-9d5d-2161f59de0ab
                The Author(s) 2023. Published by Oxford University Press on behalf of the National Academy of Sciences.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                : 22 July 2022
                : 23 December 2022
                : 03 February 2023
                Page count
                Pages: 16
                Funding
                Funded by: National Natural Science Foundation of China, DOI 10.13039/501100001809;
                Award ID: 91749129
                Award ID: 32030033
                Award ID: 31970667
                Funded by: National Key Research and Development Program of China, DOI 10.13039/501100012166;
                Award ID: 2018YFC1003004
                Categories
                Research Report
                Biological, Health, and Medical Sciences
                Cell Biology
                AcademicSubjects/MED00010
                AcademicSubjects/SCI00010
                AcademicSubjects/SOC00010
                PNAS_Nexus/cell-bio
                PNAS_Nexus/dev-bio

                ovarian aging,oocytes,cumulus cells,transcriptome,methylome
                ovarian aging, oocytes, cumulus cells, transcriptome, methylome

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