<scp>YY</scp>
            1 regulates skeletal muscle regeneration through controlling metabolic reprogramming of satellite cells

Chen, Fengyuan; Zhou, Jiajian; Li, Yuying; Zhao, Yu; Yuan, Jie; Cao, Yang; Wang, Lijun; Zhang, Zongkang; Zhang, Bao-Ting; Wang, Chi Chiu; Cheung, Tom H.; Wu, Zhenguo; Wong, Carmen Chak‐Lui; Sun, Hao; Wang, Huating

doi:10.15252/embj.201899727

Cited by 79 publications

(95 citation statements)

References 61 publications

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“…This finding is consistent with previous literature demonstrating that higher mitochondrial content is correlated with increased transcriptional activity [47,48]. Strikingly, the two negatively associated genes both play roles in innate immune function [41,42] [35][36][37][38][39]. Additionally, we found significant enrichment of signal for genes implicated in ubiquitin-mediated proteolysis and splicing.…”

Section: Discussionsupporting

confidence: 92%

“…All of these transcription factors regulate genes that play a role in mitochondrial function [35][36][37][38][39]. Gene expression levels of these transcription factors were all positively correlated with mtDNA-CN, with 5 out of 6 nominally significant, and 3 remaining significant after Bonferroni correction (p<8.33e-3) ( Table 3).…”

Section: Gene Set Enrichment Analysis Uncovers Gene Regulatory Networmentioning

confidence: 99%

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Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

Yang

Castellani

Longchamps

et al. 2020

Preprint

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Mitochondrial DNA copy number (mtDNA-CN) can be used as a proxy for mitochondrial function and is associated with a number of aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect risk for diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated the relationships between mtDNA-CN measured in whole blood and gene expression from whole blood as well as 47 additional tissues. We evaluated associations between blood-derived mtDNA-CN and gene expression in whole blood for 418 individuals, correcting for known confounders and surrogate variables derived from RNA-sequencing. Using a permutation-derived cutoff (p<2.70e-6), mtDNA-CN was significantly associated with expression for 721 genes in whole blood, including nuclear genes that are required for mitochondrial DNA replication. Significantly enriched pathways included splicing (p=1.03e-8) and ubiquitin-mediated proteolysis (p=2.4e-10). Genes with target sequences for the mitochondrial transcription factor NRF1 were also enriched (p=1.76e-35). In non-blood tissues, there were more significantly associated genes than expected in 30 out of 47 tested tissues, suggesting that global gene expression in those tissues is correlated with mtDNA-CN. Pathways that were associated in multiple tissues included RNA-binding, catalysis, and neurodegenerative disease. We evaluated the association between mtDNA-CN and incident neurodegenerative disease in an independent dataset, the UK Biobank, using a Cox proportional-hazards model. Higher mtDNA-CN was significantly associated with lower risk for incident neurodegenerative disease (HR=0.73, 95% CI= 0.66;0.90). The observation that mtDNA-CN measured in whole blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Key pathways in maintaining cellular homeostasis, including splicing, RNA binding, and catalytic genes were significantly associated with mtDNA-CN, reinforcing the importance of mitochondria in aging-related disease. As a specific example, genes involved in neurodegenerative disease were significantly enriched in multiple tissues. This finding, validated in a large independent cohort study showing an inverse association between mtDNA-CN and neurodegenerative disease, solidifies the link between blood-derived mtDNA-CN, altered gene expression in both blood and non-blood tissues, and aging-related disease.

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Section: Discussionsupporting

confidence: 92%

Section: Gene Set Enrichment Analysis Uncovers Gene Regulatory Networmentioning

confidence: 99%

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

Yang

Castellani

Longchamps

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Then, TA muscle tissues were extracted from mice with JQ1 and control DMSO‐treated mice. Meanwhile, SCs were isolated from mouse muscle by using fluorescence‐activated cell sorting (FACS) with cell surface marker Sca1 − /CD31 − /CD45 − /Vcam + (Liu, Cheung, Charville, & Rando, ; Chen et al ). The BD FACSAria Fusion cell sorter (BD Biosciences) was used for muscle SC sorting following the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells

Zhou

et al. 2019

Aging Cell

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Epigenetic alterations occur in various cells and tissues during aging, but it is not known if such alterations are also associated with aging in skeletal muscle. Here, we examined the changes of a panel of histone modifications and found H3K27ac (an active enhancer mark) is markedly increased in aged human skeletal muscle tissues. Further analyses uncovered that the H3K27ac increase and enhancer activation are associated with the up‐regulation of extracellular matrix (ECM) genes; this may result in alteration of the niche environment for skeletal muscle stem cells, also called satellite cells (SCs), which causes decreased myogenic potential and fibrogenic conversion of SCs. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation, inhibited the ECM up‐regulation and fibrogenic conversion of SCs and restored their myogenic differentiation potential. Altogether, our findings not only uncovered a novel aspect of skeletal muscle aging that is associated with enhancer remodeling but also implicated JQ1 as a potential treatment approach for restoring SC function in aging muscle.

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“…Myogenesis involves successive reprogramming of myogenic progenitors, which switch from a dormant to a proliferative state, before differentiating into mature myofibers or entering quiescence (self-renewal). Differentiation requires the acquisition of a metabolism able to sustain the high energetic cost of muscle contraction 36,43 and is accompanied with an increased resistance to apoptosis. ANT1 expression is suggested to increase upon differentiation, to sustain the switch from a glycolytic metabolism observed in myoblasts to an oxidative one in myofibers 11 .…”

Section: Discussionmentioning

confidence: 99%

Low expression of ANT1 confers oncogenic properties to rhabdomyosarcoma tumor cells by modulating metabolism and death pathways

Vial¹,

Huchedé²,

Fagault³

et al. 2020

Cell Death Discov.

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Rhabdomyosarcoma (RMS) is the most frequent form of pediatric soft-tissue sarcoma. It is divided into two main subtypes: ERMS (embryonal) and ARMS (alveolar). Current treatments are based on chemotherapy, surgery, and radiotherapy. The 5-year survival rate has plateaued at 70% since 2000, despite several clinical trials. RMS cells are thought to derive from the muscle lineage. During development, myogenesis includes the expansion of muscle precursors, the elimination of those in excess by cell death and the differentiation of the remaining ones into myofibers. The notion that these processes may be hijacked by tumor cells to sustain their oncogenic transformation has emerged, with RMS being considered as the dark side of myogenesis. Thus, dissecting myogenic developmental programs could improve our understanding of RMS molecular etiology. We focused herein on ANT1, which is involved in myogenesis and is responsible for genetic disorders associated with muscle degeneration. ANT1 is a mitochondrial protein, which has a dual functionality, as it is involved both in metabolism via the regulation of ATP/ADP release from mitochondria and in regulated cell death as part of the mitochondrial permeability transition pore. Bioinformatics analyses of transcriptomic datasets revealed that ANT1 is expressed at low levels in RMS. Using the CRISPR-Cas9 technology, we showed that reduced ANT1 expression confers selective advantages to RMS cells in terms of proliferation and resistance to stress-induced death. These effects arise notably from an abnormal metabolic switch induced by ANT1 downregulation. Restoration of ANT1 expression using a Tet-On system is sufficient to prime tumor cells to death and to increase their sensitivity to chemotherapy. Based on our results, modulation of ANT1 expression and/or activity appears as an appealing therapeutic approach in RMS management.

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YY 1 regulates skeletal muscle regeneration through controlling metabolic reprogramming of satellite cells

Cited by 79 publications

References 61 publications

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells

Low expression of ANT1 confers oncogenic properties to rhabdomyosarcoma tumor cells by modulating metabolism and death pathways

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