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      Age Alters Chromatin Structure and Expression of SUMO Proteins under Stress Conditions in Human Adipose-Derived Stem Cells

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          Abstract

          Adult stem cells play a critical role in tissue homeostasis and repair. Aging leads to a decline in stem cells’ regenerative capacity that contributes significantly to the maintenance of organ and tissue functions. Age-dependent genomic and epigenetic modifications together play a role in the disruption of critical cellular pathways. However, the epigenetic mechanisms responsible for the decline of adult stem cell functions remain to be well established. Here, we investigated age-dependent, genome-wide alterations in the chromatin accessibility of primary human adipose-derived stem cells (ASCs) in comparison to age-matched fibroblasts via ATAC-seq technology. Our results demonstrate that aging ASCs possess globally more stable chromatin accessibility profiles as compared to aging fibroblasts, suggesting that robust regulatory mechanisms maintain adult stem cell chromatin structure against aging. Furthermore, we observed age-dependent subtle changes in promoter nucleosome positioning in selective pathways during aging, concurrent with altered small ubiquitin-related modifier (SUMO) protein expression under stress conditions. Together, our data suggest a significant role for nucleosome positioning in sumoylation pathway regulation in stress response during adult stem cell aging. The differences described here between the chromatin structure of human ASCs and fibroblasts will further elucidate the mechanisms regulating gene expression during aging in both stem cells and differentiated cells.

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          Most cited references29

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          Nucleosome positioning and gene regulation: advances through genomics.

          Knowing the precise locations of nucleosomes in a genome is key to understanding how genes are regulated. Recent 'next generation' ChIP-chip and ChIP-Seq technologies have accelerated our understanding of the basic principles of chromatin organization. Here we discuss what high-resolution genome-wide maps of nucleosome positions have taught us about how nucleosome positioning demarcates promoter regions and transcriptional start sites, and how the composition and structure of promoter nucleosomes facilitate or inhibit transcription. A detailed picture is starting to emerge of how diverse factors, including underlying DNA sequences and chromatin remodelling complexes, influence nucleosome positioning.
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            Genome-scale identification of nucleosome positions in S. cerevisiae.

            G.-C. Yuan (2005)
            The positioning of nucleosomes along chromatin has been implicated in the regulation of gene expression in eukaryotic cells, because packaging DNA into nucleosomes affects sequence accessibility. We developed a tiled microarray approach to identify at high resolution the translational positions of 2278 nucleosomes over 482 kilobases of Saccharomyces cerevisiae DNA, including almost all of chromosome III and 223 additional regulatory regions. The majority of the nucleosomes identified were well-positioned. We found a stereotyped chromatin organization at Pol II promoters consisting of a nucleosome-free region approximately 200 base pairs upstream of the start codon flanked on both sides by positioned nucleosomes. The nucleosome-free sequences were evolutionarily conserved and were enriched in poly-deoxyadenosine or poly-deoxythymidine sequences. Most occupied transcription factor binding motifs were devoid of nucleosomes, strongly suggesting that nucleosome positioning is a global determinant of transcription factor access.
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              Stem cell aging: mechanisms, regulators and therapeutic opportunities.

              Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic 'memory' that is indelibly written or one that can be reset.
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                Author and article information

                Contributors
                ivona.percec@uphs.upenn.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                31 July 2018
                31 July 2018
                2018
                : 8
                : 11502
                Affiliations
                [1 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Surgery, , University of Pennsylvania, ; Philadelphia, PA 19104 USA
                [2 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Epigenetics Institute, Department of Cell and Developmental Biology, , University of Pennsylvania, ; Philadelphia, PA 19104 USA
                Article
                29775
                10.1038/s41598-018-29775-y
                6068198
                30065345
                b82738f8-fbb2-4cbb-b358-1da5481e9f2a
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 March 2018
                : 14 July 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000049, U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging);
                Award ID: K08 AG042496
                Award Recipient :
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