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      LncRNA NEAT1 controls the lineage fates of BMSCs during skeletal aging by impairing mitochondrial function and pluripotency maintenance

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          Abstract

          Aged bone marrow mesenchymal stem cells (BMSCs) exhibit aberrant self-renewal and lineage specification, which contribute to imbalanced bone-fat and progressive bone loss. In addition to known master regulators of lineage commitment, it is crucial to identify pivotal switches governing the specific differentiation fate of aged BMSCs. Here, we profiled differences in epigenetic regulation between adipogenesis and osteogenesis and identified super-enhancer associated lncRNA nuclear-enriched abundant transcript 1 (NEAT1) as a key bone-fat switch in aged BMSCs. We validated that NEAT1 with high enhancer activity was transcriptionally activated by ATF2 and directed aged BMSCs to a greater propensity to differentiate toward adipocytes than osteoblasts by mediating mitochondrial function. Furthermore, we confirmed NEAT1 as a protein-binding scaffold in which phosphorylation modification of SOX2 Ser249/250 by CDK2 impaired SOX2/OCT4 complex stability and dysregulated downstream transcription networks of pluripotency maintenance. In addition, by sponging miR-27b-3p, NEAT1 upregulated BNIP3L, BMP2K, and PPARG expression to shape mitochondrial function and osteogenic/adipogenic differentiation commitment, respectively. In extracellular communication, NEAT1 promoted CSF1 secretion from aged BMSCs and then strengthened osteoclastic differentiation by extracellular vesicle delivery. Notably, Neat1 small interfering RNA delivery induced increased bone mass in aged mice and decreased fat accumulation in the bone marrow. These findings suggest that NEAT1 regulates the lineage fates of BMSCs by orchestrating mitochondrial function and pluripotency maintenance, and might be a potential therapeutic target for skeletal aging.

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          Most cited references63

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          Multilineage potential of adult human mesenchymal stem cells.

          Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.
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            Master transcription factors and mediator establish super-enhancers at key cell identity genes.

            Master transcription factors Oct4, Sox2, and Nanog bind enhancer elements and recruit Mediator to activate much of the gene expression program of pluripotent embryonic stem cells (ESCs). We report here that the ESC master transcription factors form unusual enhancer domains at most genes that control the pluripotent state. These domains, which we call super-enhancers, consist of clusters of enhancers that are densely occupied by the master regulators and Mediator. Super-enhancers differ from typical enhancers in size, transcription factor density and content, ability to activate transcription, and sensitivity to perturbation. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. Super-enhancers thus play key roles in the control of mammalian cell identity. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Super-enhancers in the control of cell identity and disease.

              Super-enhancers are large clusters of transcriptional enhancers that drive expression of genes that define cell identity. Improved understanding of the roles that super-enhancers play in biology would be afforded by knowing the constellation of factors that constitute these domains and by identifying super-enhancers across the spectrum of human cell types. We describe here the population of transcription factors, cofactors, chromatin regulators, and transcription apparatus occupying super-enhancers in embryonic stem cells and evidence that super-enhancers are highly transcribed. We produce a catalog of super-enhancers in a broad range of human cell types and find that super-enhancers associate with genes that control and define the biology of these cells. Interestingly, disease-associated variation is especially enriched in the super-enhancers of disease-relevant cell types. Furthermore, we find that cancer cells generate super-enhancers at oncogenes and other genes important in tumor pathogenesis. Thus, super-enhancers play key roles in human cell identity in health and in disease. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                jhb@njmu.edu.cn
                Journal
                Cell Death Differ
                Cell Death Differ
                Cell Death and Differentiation
                Nature Publishing Group UK (London )
                1350-9047
                1476-5403
                8 September 2021
                8 September 2021
                February 2022
                : 29
                : 2
                : 351-365
                Affiliations
                [1 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Jiangsu Key Laboratory of Oral Diseases, , Nanjing Medical University, ; Nanjing, Jiangsu Province China
                [2 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, , Nanjing Medical University, ; Nanjing, Jiangsu Province China
                [3 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Jiangsu Key Laboratory of Cardiovascular and Cerebrovascular Medicine, , Nanjing Medical University, ; Nanjing, Jiangsu Province China
                [4 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Basic Science of Stomatology, Affiliated Hospital of Stomatology, , Nanjing Medical University, ; Nanjing, Jiangsu Province China
                [5 ]Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, Jiangsu Province China
                Author information
                http://orcid.org/0000-0002-3748-0381
                Article
                858
                10.1038/s41418-021-00858-0
                8816946
                34497381
                6a357172-0c3e-414f-b00b-9accd304be1f
                © 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 February 2021
                : 16 August 2021
                : 20 August 2021
                Funding
                Funded by: Postgraduate Research & Practice Innovation Program of Jiangsu Province(KYCX19_1149)
                Funded by: Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD, 2018-87)
                Funded by: FundRef https://doi.org/10.13039/501100004608, Natural Science Foundation of Jiangsu Province (Jiangsu Provincial Natural Science Foundation);
                Award ID: BK20201350
                Award Recipient :
                Funded by: Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD, 2018-87) Natural science foundation of the Jiangsu Higher Education Institutions of China(grants 19KJA360003)
                Categories
                Article
                Custom metadata
                © ADMC Associazione Differenziamento e Morte Cellulare 2022

                Cell biology
                gene regulation,endocrine system and metabolic diseases
                Cell biology
                gene regulation, endocrine system and metabolic diseases

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