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      Chromatin remodeling due to degradation of citrate carrier impairs osteogenesis of aged mesenchymal stem cells

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          Abstract

          Aging is accompanied by a general decline in the function of many cellular pathways. However, whether these are causally or functionally interconnected remains elusive. Here, we study the effect of mitochondrial–nuclear communication on stem cell aging. We show that aged mesenchymal stem cells exhibit reduced chromatin accessibility and lower histone acetylation, particularly on promoters and enhancers of osteogenic genes. The reduced histone acetylation is due to impaired export of mitochondrial acetyl-CoA, owing to the lower levels of citrate carrier (CiC). We demonstrate that aged cells showed enhanced lysosomal degradation of CiC, which is mediated via mitochondrial-derived vesicles. Strikingly, restoring cytosolic acetyl-CoA levels either by exogenous CiC expression or via acetate supplementation, remodels the chromatin landscape and rescues the osteogenesis defects of aged mesenchymal stem cells. Collectively, our results establish a tight, age-dependent connection between mitochondrial quality control, chromatin and stem cell fate, which are linked together by CiC.

          Abstract

          Aged mesenchymal stem cells exhibit decreased osteogenesis. Pouikli et al. link impaired MSC differentiation to histone hypoacetylation caused by lower mitochondrial acetyl-CoA export due to enhanced lysosomal degradation of the citrate carrier Slc25a1. Restoring histone acetylation to youthful levels rescues osteogenesis.

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          The Sequence Alignment/Map format and SAMtools

          Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
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            STAR: ultrafast universal RNA-seq aligner.

            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. 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. 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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              Fast gapped-read alignment with Bowtie 2.

              As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.
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                Author and article information

                Contributors
                ptessarz@age.mpg.de
                Journal
                Nat Aging
                Nat Aging
                Nature Aging
                Nature Publishing Group US (New York )
                2662-8465
                13 September 2021
                13 September 2021
                2021
                : 1
                : 9
                : 810-825
                Affiliations
                [1 ]GRID grid.419502.b, ISNI 0000 0004 0373 6590, Max-Planck Research Group Chromatin and Ageing, , Max Planck Institute for Biology of Ageing, ; Cologne, Germany
                [2 ]GRID grid.419502.b, ISNI 0000 0004 0373 6590, Department of Biological Mechanisms of Ageing, , Max Planck Institute for Biology of Ageing, ; Cologne, Germany
                [3 ]GRID grid.266190.a, ISNI 0000000096214564, Computer Science, , University of Colorado, ; Boulder, CO USA
                [4 ]GRID grid.266190.a, ISNI 0000000096214564, BioFrontiers Institute, , University of Colorado, ; Boulder, CO USA
                [5 ]GRID grid.419502.b, ISNI 0000 0004 0373 6590, FACS & Imaging Core Facility, , Max Planck Institute for Biology of Ageing, ; Cologne, Germany
                [6 ]GRID grid.419502.b, ISNI 0000 0004 0373 6590, Metabolomics Core Facility, , Max Planck Institute for Biology of Ageing, ; Cologne, Germany
                [7 ]GRID grid.419502.b, ISNI 0000 0004 0373 6590, Phenotyping Core Facility, , Max Planck Institute for Biology of Ageing, ; Cologne, Germany
                [8 ]GRID grid.8217.c, ISNI 0000 0004 1936 9705, Trinity Centre for Biomedical Engineering, , Trinity Biomedical Sciences Institute, Trinity College Dublin, ; Dublin, Ireland
                [9 ]GRID grid.8217.c, ISNI 0000 0004 1936 9705, Department of Mechanical, Manufacturing and Biomedical Engineering, , School of Engineering, Trinity College Dublin, ; Dublin, Ireland
                [10 ]GRID grid.4912.e, ISNI 0000 0004 0488 7120, Advanced Materials and Bioengineering Research Centre (AMBER), , Royal College of Surgeons in Ireland and Trinity College Dublin, ; Dublin, Ireland
                [11 ]GRID grid.266190.a, ISNI 0000000096214564, Molecular, Cellular and Developmental Biology, , University of Colorado, ; Boulder, CO USA
                [12 ]GRID grid.452408.f, Cologne Excellence Cluster on Stress Responses in Ageing-Associated Diseases (CECAD), ; Cologne, Germany
                Author information
                http://orcid.org/0000-0001-7982-7737
                http://orcid.org/0000-0003-3518-7074
                http://orcid.org/0000-0001-5898-0409
                http://orcid.org/0000-0001-9615-0094
                http://orcid.org/0000-0002-6953-9835
                Article
                105
                10.1038/s43587-021-00105-8
                10154229
                37117628
                c18265aa-7051-4ff3-8657-8983887a0715
                © The Author(s) 2021

                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
                : 28 August 2020
                : 26 July 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100005302, Alexander S. Onassis Public Benefit Foundation (Onassis Foundation);
                Award ID: 047-1/2019-2020
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100005156, Alexander von Humboldt-Stiftung (Alexander von Humboldt Foundation);
                Funded by: FundRef https://doi.org/10.13039/100000057, U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS);
                Award ID: GM125871
                Award ID: GM125871
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100010663, EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council);
                Award ID: ERC336882
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001602, Science Foundation Ireland (SFI);
                Award ID: SFI12/RC/2278_2
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004189, Max-Planck-Gesellschaft (Max Planck Society);
                Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);
                Award ID: EXC2030/1
                Award Recipient :
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                © The Author(s), under exclusive licence to Springer Nature America, Inc. 2021

                chromatin structure,histone post-translational modifications,ageing,adult stem cells,mitochondria

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